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Local, but not systemic, administration of serotonergic antidepressants decreases hippocampal nitric oxide synthase activity
Abstract
Nitric oxide (NO) is an unconventional transmitter molecule in the nervous system, synthesized by nitric oxide synthase (NOS) following activation of the N-methyl-D-aspartate (NMDA) receptor. Several in vivo studies have demonstrated that NO modulates the extracellular levels of various neurotransmitters in the central nervous system, while serotonin (5-HT) re-uptake may be influenced by the NO pathway. Moreover, inhibitors of NOS exhibit antidepressant-like and anxiolytic-like properties in various animal models. Therefore, the aims of the present study were to clarify the involvement of distinct antidepressants acting on the serotonin re-uptake site in the regulation of the activity of hippocampal NOS in vitro, in vivo and ex vivo. We found that citalopram, paroxetine, imipramine and N(G)-nitro-L-arginine dose dependently decreased the hippocampal NOS activity in vitro. Moreover, local administration of citalopram, paroxetine, tianeptine, imipramine and N(G)-nitro-L-arginine significantly decreased the hippocampal NOS activity in vivo at a concentration significantly lower than in vitro. No effect on NOS activity following retrodialysis with 5-HT was observed. Acute (5 mg/kg, s.c.) and chronic (3 weeks, 20 mg/kg/24 h) systemic administration of citalopram did not influence NOS activity ex vivo. The effects on NOS represent a response to structurally dissimilar serotonergic antidepressants. However, since these data reflect effects on basal NOS activity, we believe that serotonergic antidepressants do not directly affect NOS at dosages used clinically, but the findings may reflect a secondary action of antidepressants on the glutamate NMDA receptor following their primary inhibitory action at the 5-HT transporter.
... 26 Since the NO-cyclic guanosine monophosphate (cGMP) pathway represents a possible biological target in treating depression, 27,28 these actions may contribute to its observed antidepressant response. [29][30][31][32] In support of this, a number of antidepressants are known to inhibit NOS. 32,33 MB also is a noteworthy inhibitor of monoamine oxidase (MAO) A, 12,34,35 while MAO inhibition is a well-established mechanism of antidepressant action. ...
... [29][30][31][32] In support of this, a number of antidepressants are known to inhibit NOS. 32,33 MB also is a noteworthy inhibitor of monoamine oxidase (MAO) A, 12,34,35 while MAO inhibition is a well-established mechanism of antidepressant action. 36 Since MAO-A is a key enzyme in the regulation of central serotonin levels, MAO-A inhibition is associated with an antidepressant effect. ...
... citalopram, tianeptine, imipramine, paroxetine) inhibit NOS. 32 It should also be noted that NOS inhibition increases serotonin and dopamine release, and thus present with a risk of inducing ST. 53 Low potency MAO-A inhibition by these synthetic analogues may, however, still be of relevance to the treatment of depression. In this regard, the observation that toloxatone, an MAO-A inhibitor with clinically useful antidepressant effects, presents with an IC 50 of 6.7 µM which suggests that our newly synthesized compounds (with similar or better potencies) may still possess clinically relevant therapeutic effects based on their MAO inhibition properties. ...
Methylene blue (MB) possesses diverse medical applications. Among these MB presents with antidepressant-like effects in animals and has shown promise in clinical trials for the treatment of mood disorders. As an antidepressant, MB may act via various mechanisms which include modulation of the nitric oxide cyclic guanosine monophosphate (NO-cGMP) cascade, enhancement of mitochondrial respiration and antioxidant effects. MB is also, however, a high potency inhibitor of monoamine oxidase (MAO) A, which most likely contributes to its antidepressant effect, but also to its adverse effects profile (eg. serotonin toxicity). The latter has raised the question whether it is possible to design out the MAO inhibition properties of MB yet retaining the clinically useful attributes. This study explores this idea further by characterizing five newly synthesized MB analogues and examining their antidepressant-like properties in the acute forced swim test (FST) in rats, with comparison to imipramine and MB. The results show that all five analogues exhibit antidepressant-like properties in the FST without confounding effects on locomotor activity. The magnitude of these effects is comparable to those of imipramine and MB. Since these newly synthesized MB analogues are markedly less potent MAO-A inhibitors (IC50 = 0.518–4.73 µM) than MB (IC50 = 0.07 µM), we postulate that such lower potency MAO-A inhibitors may present with a reduced risk of adverse effects associated with MAO-A inhibition. While low level MAO-A inhibition still may produce an antidepressant effect, we posit that other MB-related mechanisms may underlie their antidepressant effects, thereby representing a novel group of antidepressant compounds.
... Moreover, the administration of NOS inhibitors not only increases the efflux of serotonin and dopamine in the hippocampus of rats (Wegener et al. 2000), thus reversing the adverse effects of NO on biogenic amine transmission, but are also effective in paradigms of depression (Harkin et al. 1999) and anxiety (Volke et al. 1997) in animals. Finally, a number of studies have demonstrated that various classes of antidepressants inhibit NOS, such as citalopram (Wegener et al. 2003), paroxetine (Finkel et al. 1996), imipramine (Harvey et al. 2006) and tianeptine (Wegener et al. 2003). ...
... Moreover, the administration of NOS inhibitors not only increases the efflux of serotonin and dopamine in the hippocampus of rats (Wegener et al. 2000), thus reversing the adverse effects of NO on biogenic amine transmission, but are also effective in paradigms of depression (Harkin et al. 1999) and anxiety (Volke et al. 1997) in animals. Finally, a number of studies have demonstrated that various classes of antidepressants inhibit NOS, such as citalopram (Wegener et al. 2003), paroxetine (Finkel et al. 1996), imipramine (Harvey et al. 2006) and tianeptine (Wegener et al. 2003). ...
... As mentioned before, various studies have implicated the NO-cGMP cell signalling pathway in the neurobiology of depression (Suzuki et al. 2001;Bernstein et al. 1998;) and in the response to antidepressant drugs (Wegener et al. 2003). As an inhibitor of GC, MB has been widely used for this purpose in pharmacological experiments to demonstrate cGMP-mediated processes (Gruetter et al. 1981;Ignarro and Kadowitz 1985;Iadecola et al. 1995;Harvey and Bester 2000). ...
Methylene Blue (MB) is considered to have diverse medical applications and is a well-described treatment for methemoglobinemias and ifosfamide-induced encephalopathy. In recent years the focus has shifted to MB as an antimalarial agent and as a potential treatment for neurodegenerative disorders such as Alzheimer’s disease. Of interest are reports that MB possesses antidepressant and anxiolytic activity in pre-clinical models and has shown promise in clinical trials for schizophrenia and bipolar disorder. MB is a noteworthy inhibitor of monoamine oxidase A (MAO-A), which is a well-established target for antidepressant action. MB is also recognized as a non-selective inhibitor of nitric oxide synthase (NOS) and guanylate cyclase. Dysfunction of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) cascade is strongly linked to the neurobiology of mood, anxiety and psychosis, while the inhibition of NOS and/or guanylate cyclase has been associated with an antidepressant response. This action of MB may contribute significantly to its psychotropic activity. However, these disorders are also characterised by mitochondrial dysfunction and redox imbalance. By acting as an alternative electron acceptor/donor MB restores mitochondrial function, improves neuronal energy production and inhibits the formation of superoxide, effects that also may contribute to its therapeutic activity. Using MB in depression co-morbid with neurodegenerative disorders, like Alzheimer’s and Parkinson’s disease, also represents a particularly relevant strategy. By considering their physicochemical and pharmacokinetic properties, analogues of MB may provide therapeutic potential as novel multi-target strategies in the treatment of depression. In addition, low MAO-A active analogues may provide equal or improved response with a lower risk of adverse effects.
... There are several indications for the involvement of the Glu/NMDAR/NO/cGMP pathway in the pathophysiology of depression as well as in the action of antidepressants. For example, depressed patients exhibit elevated plasma nitrate levels (9), whereas pre-clinical studies have demonstrated antidepressant-like effects following the local or systemic administration of NOS inhibitors (10)(11)(12)(13)(14)(15)(16). Furthermore, the Glu/NMDAR/NO/cGMP pathway has been shown to be involved in the antidepressantlike activity of a range of different drugs using rodent models (11)(12)(13)(17)(18)(19)(20)(21)(22). ...
... For example, depressed patients exhibit elevated plasma nitrate levels (9), whereas pre-clinical studies have demonstrated antidepressant-like effects following the local or systemic administration of NOS inhibitors (10)(11)(12)(13)(14)(15)(16). Furthermore, the Glu/NMDAR/NO/cGMP pathway has been shown to be involved in the antidepressantlike activity of a range of different drugs using rodent models (11)(12)(13)(17)(18)(19)(20)(21)(22). The specific brain area(s) that are involved in these effects remain unclear, but it appears that the hippocampus may play an important role. ...
... The specific brain area(s) that are involved in these effects remain unclear, but it appears that the hippocampus may play an important role. For instance, the intra-hippocampal injection of an NMDA receptor antagonist (23) or a selective nNOS inhibitor (14,24) produces antidepressant-like effects, whereas local administration of serotonergic antidepressants reduces hippocampal NOS activity in rats (11). ...
We investigated whether the nitric oxide (NO) precursor, l-arginine, can prevent the antidepressant-like action of the fast-acting antidepressant, ketamine, in a genetic rat model of depression, and/or induce changes in the glutamate (Glu)/N-methyl-d-aspartate receptor (NMDAR)/NO/cyclic guanosine monophosphate (cGMP) signalling pathway. Hereby it was evaluated whether the NO signalling system is involved in the antidepressant mechanism of ketamine.
Flinders sensitive line (FSL) rats received single i.p. injections of ketamine (15 mg/kg) with/without pre-treatment (30 min prior) with l-arginine (500 mg/kg). Depression-like behaviour was assessed in the forced swim test (FST) in terms of immobility, and the activation state of the Glu/NMDAR/NO/cGMP pathway was evaluated ex vivo in the frontal cortex and hippocampus regions in terms of total constitutive NOS (cNOS) activity and cGMP concentration.
l-Arginine pre-treatment prevented the antidepressant-like effect of ketamine in the FST, as well as a ketamine-induced increase in cGMP levels in the frontal cortex and hippocampus of FSL rats. Ketamine reduced cNOS activity only in the hippocampus, and this effect was not reversed by l-arginine.
Both the behavioural and molecular results from this study indicate an involvement for the NO signalling pathway in the antidepressant action of ketamine. Although not easily interpretable, these findings broaden our knowledge of effects of ketamine on the NO system.
... NO has been involved in many signaling pathways related to stress and MDD, as well as to the antidepressant activity of classical drugs (Hiroaki-Sato et al., 2014;Joca & Guimarães, 2006;Wegener et al., 2003). Corroborating the results from the present study, pharmacological inhibition of NOS induces antidepressant-like effects in the learned helplessness paradigm (Stanquini et al., 2017) and other models, such as forced swimming test (Ferreira et al., 2012;Montezuma et al., 2012;Sales et al., 2017) and unpredictable chronic stress (Yazir et al., 2012). ...
... Corroborating the results from the present study, pharmacological inhibition of NOS induces antidepressant-like effects in the learned helplessness paradigm (Stanquini et al., 2017) and other models, such as forced swimming test (Ferreira et al., 2012;Montezuma et al., 2012;Sales et al., 2017) and unpredictable chronic stress (Yazir et al., 2012). Furthermore, activation and expression levels of NOS is attenuated by treatment with antidepressant drugs (Bollinger et al., 2017;Dhir & Kulkarni, 2007;Finkel et al., 1996;Wegener et al., 2003;Zhou et al., 2011;Zomkowski et al., 2010). Accordingly, MDD patients treated with selective serotonin reuptake inhibitors (SSRI) present a decrease of nitrate levels in the blood (Finkel et al., 1996), and rodents treated with SSRIs exhibit a reduction in the NOS activity in the brain (Krass et al., 2011). ...
It has been postulated that the activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr‐induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress‐induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed an increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre‐treatment with nNOS inhibitor nω‐propyl‐l‐arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7‐NI and aminoguanidine (AMG) decreased the number of escape failures in LH and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus.
... NO has been involved in many signaling pathways related to stress and MDD, as well as to the antidepressant activity of classical drugs (Wegener et al., 2003;Joca & Guimarães, 2006;Wegener & Volke, 2010;Hiroaki-Sato et al., 2014). Corroborating the results from the present study, pharmacological inhibition of NOS induces antidepressant-like effects in the learned helplessness paradigm (Stanquini et al., 2017) and other models, such as forced swimming test (Ferreira et al., 2012;Montezuma et al., 2012;Sales et al., 2017) and unpredictable chronic stress (Yazir et al., 2012). ...
... Corroborating the results from the present study, pharmacological inhibition of NOS induces antidepressant-like effects in the learned helplessness paradigm (Stanquini et al., 2017) and other models, such as forced swimming test (Ferreira et al., 2012;Montezuma et al., 2012;Sales et al., 2017) and unpredictable chronic stress (Yazir et al., 2012). Furthermore, activation and expression levels of NOS is attenuated by treatment with antidepressant drugs (Finkel et al., 1996;Wegener et al., 2003;Dhir & Kulkarni, 2007Zomkowski et al., 2010;Zhou et al., 2011;Bollinger et al., 2017). Accordingly, MDD patients treated with selective serotonin reuptake inhibitors (SSRI) present a decrease of nitrate levels in the blood (Finkel et al., 1996), and rodents treated with SSRIs exhibit a reduction in the NOS activity in the brain (Krass et al., 2011). ...
It has been postulated that activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr-induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress-induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre-treatment with nNOS inhibitor nω-propyl-L-arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased of DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7-NI and aminoguanidine (AMG) decreased the number of escape failures in LH, and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus.
... Since the first report by Jefferys and Funder (18), showing that systemic administration of NOS inhibitor reduces immobility time in the rat forced swimming test, several additional studies have confirmed an antidepressant-like effect in response to treatment with different NOS inhibitors in animals submitted to different models predictive of antidepressant activity (19)(20)(21)(22)(23)(24). Besides, antidepressants drugs are able to reduce NOS activity in hippocampus (25) while the discontinuation with imipramine treatment induces opposite effects in rats (26). There is also clinical evidence supporting the involvement of NO in the neurobiology of depression (27)(28)(29). ...
... Previous evidence suggests nNOS inhibitors increase serotonin availability in the hippocampus (91) and serotonin mediates their antidepressant-like Repeated treatment with nitric oxide synthase inhibitor attenuates effect in the Forced Swimming Test (FST) (92). On the other hand, different classes of antidepressants can decrease hippocampal NOS activity in vivo and in vitro (25), indicating there is a complex interaction between the nitrergic and serotonergic systems. Altogether, it is possible to suggest that the behavioural and molecular effects of 7-NI in the LH model could involve the modulation of serotonergic neurotransmission. ...
Background
Nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects in animal models sensitive to acute drug treatment such as the forced swimming test. However, it is not yet clear if repeated treatment with these drugs is required to induce antidepressant-like effects in preclinical models.
Objective
The aim of this study was to test the effect induced by acute or repeated (7 days) treatment with 7-nitroindazole (7-NI), a preferential inhibitor of neuronal NOS, in rats submitted to the learned helplessness (LH) model. In addition, we aimed at investigating if 7-NI treatment would increase brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus, similarly to the effect of prototype antidepressants.
Methods
Animals were submitted to a pre-test (PT) session with inescapable footshocks or habituation (no shocks) to the experimental shuttle box. Six days later they were exposed to a test with escapable footshocks. Independent groups received acute (a single injection after PT or before test) or repeated (once a day for 7 days) treatment with vehicle or 7-NI (30 mg/kg).
Results
Repeated, but not acute, treatment with 7-NI attenuated LH development. The effect was similar to repeated imipramine treatment. Moreover, in an independent experimental group, only repeated treatment with 7-NI and imipramine increased BDNF protein levels in the hippocampus.
Conclusion
The results suggest the nitrergic system could be a target for the treatment of depressive-like conditions. They also indicate that, similar to the positive control imipramine, the antidepressant-like effects of NOS inhibition could involve an increase in hippocampal BDNF levels.
... These results suggest that tianeptine may possess neuroprotective effects against hypoxia via a mechanism different from NMDA channel inhibition and may protect against the deleterious effects of cytokines [137]. Of particular significance is that tianeptine has been found to inhibit the activity of nitric oxide synthase (NOS) in the hippocampus [138], an important subcellular signaling system for the glutamate-NMDA receptor. Nitric oxide (NO) is a recognized neurotoxin, which has been found to be elevated in depressed patients [139] and which may underlie the neuroprotective actions of tianeptine. ...
... Furthermore, inhibition of NOS may also be directly involved in the antidepressant actions of tianeptine, since NOS inhibitors have distinct antidepressant activity in animal models [140]. It should, however, be noted that various classes of antidepressants, including tricyclics and SSRIs, inhibit NOS, in addition to established actions on serotonin, suggesting a cross-talk between serotoninglutamate-NO in antidepressant action [138]. These findings should be read in conjunction with the suggestion of the modulating effect of tianeptine at AMPA/kainate type glutamate receptors, as mentioned in the discussion of the patent above. ...
... The possible mechanisms whereby NO can contribute to mood disorders is obscure, although persistent research has highlighted various possibilities including the actions of the NO/cyclic guanosine 3'5'monophosphate (cGMP) pathway. Modulators of the NOpathway have also gained relevance in MD research due to NO-inhibitors demonstrating antidepressant effects in models predictive of antidepressant activity [227,228]. By activating soluble guanylate cyclase (sGC) which converts guanosine 5'-triphosphate (GTP) to the intracellular messenger cGMP [229,230], NO is enabled to mediate many cellular processes, particularly the regulation of ion channels, activation and inhibition of cyclic nucleotide hydrolysis by phosphodiesterase, activation of G-kinase and modulation of neurotransmitter release [229,231]. ...
... methylene blue) [232] as well as PDE 5 inhibitors (e.g. sildenafil) [233] have antidepressant and anxiolytic effects in animal models [234,235] (Fig. 1), as do clinically relevant antidepressants [228]. These effects however are due to interference with constitutive nNOS-mediated effects and not inducible NOS (iNOS), which rather plays an important role in chronic stress associated with inflammation [231] ( Fig. 1). ...
Despite significant research efforts aimed at understanding the neurobiological underpinnings of mood (depression, bipolar disorder) and psychotic disorders, the diagnosis and evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms as well as psychometric evaluations. Therefore, biological markers aimed at improving the current classification of psychotic and mood-related disorders, and that will enable patients to be stratified on a biological basis into more homogeneous clinically distinct subgroups, are urgently needed. The attainment of this goal can be facilitated by identifying biomarkers that accurately reflect pathophysiologic processes in these disorders. This review postulates that the field of psychotic and mood disorder research has advanced sufficiently to develop biochemical hypotheses of the etiopathology of the particular illness and to target the same for more effective disease modifying therapy. This implies that a “one-size fits all” paradigm in the treatment of psychotic and mood disorders is not a viable approach, but that a customized regime based on individual biological abnormalities would pave the way forward to more effective treatment. In reviewing the clinical and preclinical literature, this paper discusses the most highly regarded pathophysiologic processes in mood and psychotic disorders, thereby providing a scaffold for the selection of suitable biomarkers for future studies in this field, to develope biomarker panels, as well as to improve diagnosis and to customize treatment regimens for better therapeutic outcomes.
... 27 Pre-clinical studies have confirmed the antidepressantlike properties of NOS inhibitors 52 while various clinically effective antidepressants inhibit NOS. 53 Of special note is that NMDA antagonists and NOS inhibitors can augment the antidepressant action of typical antidepressants 54;55 suggesting that the less than adequate efficacy of current antidepressant in treating depression may be due to a relative shortfall in NMDA-NOS activity. Unfortunately, selective NOS inhibitors are unsuitable for clinical use but it is of interest that these compounds elicit antidepressant-like activity through a 5HT dependent mechanism 56 , effectively relating actions on NOS to the 5HT hypothesis of depression. ...
... It is noteworthy that a recent clinical study has described the involvement of the NO-pathway in patients with acute PTSD 92 , while the drugs of choice in the treatment of PTSD, the SRI's 7;12 , have been found to inhibit hippocampal NOS. 53 Moreover, D-cycloserine, a partial agonist at the glycine regulatory site on the NMDA receptor has demonstrated clinical efficacy in treating PTSD. 93 These studies provide a strong rationale that the NMDA receptor and its down-stream events represent an important pharmacological and therapeutic target for the treatment of PTSD. ...
Anxiety and mood disorders are amongst the most prevalent and disabling of all the psychiatric disorders. Under-diagnosis and current treatments that are often less than adequately effective, contributes to an enormous personal and economic cost to the patient, family and health-care organizations. Although distinctly separate disorders at neuropathological and phenomenological levels, brain-imaging studies in posttraumatic stress disorder (PTSD) and depression have emphasized that both illnesses may induce damaging effects on regions of the brain involved in regulating the response to stress. While controversy prevails as to whether these changes represent an adaptive process or are indeed pathological, they are associated with marked changes in memory and other cognitive functions. In depression, a history of prior episodes is correlated with a higher risk of relapse, while poor compliance with antidepressants not only predicts later relapse, it may result in a more rapid shrinkage of the abovementioned brain regions, possibly providing a basis for relapse and treatment resistance. Similarly, even with the introduction of effective medications for PTSD, many patients remain treatment-resistant. Stress in various guises may alter synaptic connectivity in the brain by bolstering glutamatergic excitotoxic mechanisms. Understanding these mechanisms may assist in developing more effective treatment strategies. This paper will review pre-clinical and clinical evidence supporting a role for the glutamatenitric oxide pathway as a putative mediator of the neuropathological changes evident in depression and stress-related disorders, particularly PTSD, and its potential as a novel target for psychotropic activity. South African Psychiatry Review Vol. 9(3) 2006: 132-139
... Moreover, altered levels of proinflammatory cytokines have been observed in patients with OCD (Endres et al., 2022). Anti-OCD interventions like SSRIs and agmatine have been shown to inhibit the levels of NOS, as indicated in a few studies (Angulo et al., 2001;Luo and Tan, 2001;Wegener et al., 2003;Gawali et al., 2016). Additionally, SCFAs, colon histology, and gut microbiota were evaluated using gas chromatography-mass spectrometry (GC-MS), hematoxylin and eosin (H&E), Alcian-blue periodic acid Schiff (PAS) staining, and 16S rRNA gene sequencing, respectively. ...
Obsessive-compulsive disorder (OCD) is a disabling mental condition that poses recurring bothersome intrusive thoughts, obsessions, and compulsions. Considering the positive impact of probiotics on neuropsychiatric disorders, herein, we investigated the effect of multistrain probiotic (Bifidobacterium lactis UBBLa-70, Bacillus coagulans Unique IS-2, Lactobacillus rhamnosus UBLR-58, Lactobacillus plantarum UBLP-40, Bifidobacterium infantis UBBI-01, Bifidobacterium breve UBBr-01, and glutamine) in the management of OCD-like phenotype in rats. Rats injected with quinpirole for 5 weeks showed an increased number of marble burying and self-grooming episodes. Quinpirole-injected animals also did less head dipping in the hole board test and avoided exploration of open spaces in the elevated-plus maze. These repetitive, compulsive, self-directed, and anxiety-like phenotypes were abolished after 8-week of multistrain probiotic treatment. Our probiotic formulation also prevented the elevated mRNA expression of interleukin-6, tumor-necrosis factor-α, and C-reactive protein in the amygdala and dysregulated levels of 5-hydroxytryptamine, dopamine, and noradrenaline in the frontal cortex of quinpirole-injected rats. The level of brain-derived neurotrophic factor in the frontal cortex remained unaffected across the groups. The altered levels of goblet cells and crypt-to-villi ratio in quinpirole rats were prevented by multistrain probiotic treatment. The results of 16S-rRNA gene-sequencing of gut microbiota from feces contents revealed an elevation in the abundance of Allobaculum and Bifidobacterium species (specifically Bifidobacterium animalis), while the presence of Lactobacillus species (including Lactobacillus reuteri and Lactobacillus vaginalis) exhibited a decline in quinpirole-induced rats. These results imply that modifying the gut-brain axis may be a possible mechanism by which selective multistrain probiotic therapy prevents OCD-like behaviors.
... Therefore, the involvement antidepressants acting on the serotonin reuptake site has been investigated in the regulation of the activity of hippocampal NOS in vitro, in vivo and ex vivo. Citalopram, paroxetine, imipramine and N(G)-nitro-L-arginine decrease the hippocampal NOS activity in vitro in a dose-dependent manner (Wegener et al 2003). The effects on NOS represent a response to structurally dissimilar serotonergic antidepressants. ...
This report describes the latest concepts of the role of nitric oxide (NO) in health and disease as a basis for therapeutics and development of new drugs. Major segments of the market for nitric oxide-based drugs are described as well as the companies involved in developing them.
Nitric oxide (NO) can generate free radicals as well as scavenge them. It also functions as a signaling molecule and has an important role in the pathogenesis of several diseases. A major focus is delivery of NO by various technologies. Another approach is modulation of nitric oxide synthase (NOS), which converts L-arginine to NO. NOS can be stimulated as well as inhibited by pharmacological and gene therapy approaches.
Important therapeutic areas for NO-based therapies are inflammatory disorders, cardiovascular diseases, erectile dysfunction, inflammation, pain and neuroprotection. The first therapeutic use of NO was by inhaltion for acute respiratory distress syndrome (ARDS). NO-donors, NO-mimics and NOS modulators are described and compared along with developmental status. NO-related mechanisms of action in existing drugs are identified.
Various pharmacological approaches are described along with their therapeutic relevance. Various approaches are compared using SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis. NO-based therapies are compared with conventional approaches and opportunities for combination with modern biotechnology approaches are described.
Share of drugs where NO is involved in the mechanism of action is analyzed in the worldwide pharmaceutical market for 2020 and is projected to 2025 and 2030 as new drugs with NO-based mechanisms are introduced into the market. Various strategies for developing such drugs are discussed.
Several companies have a product or products involving NO and free radicals. The report includes profiles of 36 companies involved in this area of which 10 have a significant interest in NO-based therapeutics. Other players are pharmaceutical and biotechnology companies as well as suppliers of products for NO research. Unfulfilled needs in the development of NO-based therapeutics are identified. Important 18 collaborations in this area are tabulated.
There are numerous publications relevant to NO. Selected 500 references are included in the bibliography. The text is supplemented with 26 tables and 30 figures. It is concluded that the future prospects for NO-based therapies are bright and fit in with biotechnology-based approaches to modern drug discovery and development. It is anticipated that some of these products will help in meeting the unfulfilled needs in human therapeutics.
... In summary, these results indicate that 3B exerts beneficial efficacy in reversing LPS-induced depressive-like behavior and reduced neuroinflammatory markers. Earlier studies show that the reduction of NO levels in the brain leads to an antidepressant effect by modulating the neurotransmitter systems; dopamine and serotonin and molecules targeting oxidative stress are of great clinical value [44,55]. Moreover, clinical findings suggested that treatments focused on reducing the levels of IL-6 may open new opportunities for patients that poorly response to pharmacological treatemnet [56]. ...
There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT6 receptor. Such a combination aimed to curb neuroinflammation, remodel GABA-ergic signaling, and provide antidepressant-like activity. The most promising hybrid 3B exerted nanomolar affinity for 5-HT6 receptors and exerted agonistic properties on GABA-A receptors. Developability studies conferred that 3B exerted favorable drug-like properties and optimal brain penetration. In in vivo studies, 3B exerted robust antidepressant-like activity and proved to be highly effective in reducing levels of oxidative stress markers and the pro-inflammatory cytokine IL-6. The inetersting pharmacological profile of 3B makes it a promising candidate for further development for depression associated with neuroinflammation.
... Some evidence has shown that lowering nitric oxide levels in the hippocampus can induce antidepressant-like effects by increasing stress-coping activity, thereby confirming that endogenous hippocampal nitric oxide plays a role in the neurobiology of stress and depression [7,11]. Literature data indicate that nitric oxide synthase inhibitors increased extracellular serotonin and dopamine levels in the rat ventral hippocampus, while L-arginine acted the opposite, thereby demonstrating the role of endogenous nitric oxide in regulating serotonin and dopamine levels in the hippocampus [12]. ...
Stress that can occur at different levels of a person’s life can cause and exacerbate various diseases. Oxidative stress and inflammation underlie this process at the cellular level. There is an urgent need to identify new and more effective therapeutic targets for the treatment of stress-induced behavioral disorders and specific drugs that affect these targets. Isatis tinctoria L. is a herbaceous species in the Brassicaceae family. Due to its potential antioxidant, nitric oxide- (NO-) inhibiting, anti-inflammatory, and neuroprotective properties, I. tinctoria could be used to treat depression, anxiety, and stress resistance. Hence, the present study is aimed at delineating whether administration of I. tinctoria leaf extract may improve stress-induced disorders in mice. A set of four behavioral tests was selected that together are suitable for phenotyping acute restraint stress-associated behaviors in mice, namely locomotor activity, social integration, dark/light box, and splash tests. The plasma and brains were collected. A brain-derived neurotrophic factor, tumor necrosis factor-alpha, C-reactive protein, corticosterone, NO, reactive oxygen species levels, superoxide dismutase and catalase activity, and ferric-reducing antioxidant power were measured. In mice stressed by immobilization, decreased locomotor activity, anxiety-like behavior, and contact with other individuals were observed, as well as increased oxidative stress and increased levels of nitric oxide in the brain and plasma C-reactive protein. A single administration of I. tinctoria leaf extract was able to reverse the behavioral response to restraint by a mechanism partially dependent on the modulation of oxidative stress, neuroinflammation, and NO reduction. In conclusion, Isatis tinctoria hydroalcoholic leaf extract can reduce stress-induced behavioral disturbances by regulating neurooxidative, neuronitrosative, and neuroimmune pathways. Therefore, it could be recommended for further research on clinical efficacy in depression and anxiety disorder treatment.
... Modulators of NO and cGMP signalling exert antidepressant effects in patients with MDD or in animal studies [147]. In fact, NO and cGMP signalling is targeted by a variety of known antidepressants in animal models of depression [148]. Not surprising too, COX-2 inhibitors may have value in bipolar disorder and as adjunctive treatments in treatment resistant depression [149,150]. ...
The recent outbreak of the corona virus disease (COVID-19) has had major global impact. The relationship between severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection and psychiatric diseases is of great concern, with an evident link between corona virus infections and various central and peripheral nervous system manifestations. Unmitigated neuro-inflammation has been noted to underlie not only the severe respiratory complications of the disease but is also present in a range of neuro-psychiatric illnesses. Several neurological and psychiatric disorders are characterized by immune-inflammatory states, while treatments for these disorders have distinct anti-inflammatory properties and effects. With inflammation being a common contributing factor in SARS-CoV-2, as well as psychiatric disorders, treatment of either condition may affect disease progression of the other or alter response to pharmacological treatment. In this review, we elucidate how viral infections could affect pre-existing psychiatric conditions and how pharmacological treatments of these conditions may affect overall progress and outcome in the treatment of SARS-CoV-2. We address whether any treatment-induced benefits and potential adverse effects may ultimately affect the overall treatment approach, considering the underlying dysregulated neuro-inflammatory processes and potential drug interactions. Finally, we suggest adjunctive treatment options for SARS-CoV-2-associated neuro-psychiatric symptoms.
... Considering a possible involvement in OCD, inhibition of NO synthesis prevents excessive marble-burying behavior (Krass et al., 2010), a behavioral marker of compulsive behavior in rodents. In a related study, Umathe et al. (2009a) found that OC behaviors in mice appear related to increased levels of NO in brain, whereas the anticompulsive effects of paroxetine are related to the drug's ability to decrease brain levels of NO (Finkel et al., 1996;Wegener et al., 2003). Consistent with these results in animals, studies in patients with OCD have shown significantly elevated plasma nitrate levels (NO 3 2 ), a stable marker of NO, that were positively correlated with YBOCS scores (Atmaca et al., 2005). ...
This review evaluates current knowledge about obsessive-compulsive disorder (OCD), with the goal of providing a roadmap for future directions in research on the psychopharmacology of the disorder. It first addresses issues in the description and diagnosis of OCD, including the structure, measurement, and appropriate description of the disorder and issues of differential diagnosis. Current pharmacotherapies for OCD are then reviewed, including monotherapy with serotonin reuptake inhibitors and augmentation with antipsychotic medication and with psychologic treatment. Neuromodulatory therapies for OCD are also described, including psychosurgery, deep brain stimulation, and noninvasive brain stimulation. Psychotherapies for OCD are then reviewed, focusing on behavior therapy, including exposure and response prevention and cognitive therapy, and the efficacy of these interventions is discussed, touching on issues such as the timing of sessions, the adjunctive role of pharmacotherapy, and the underlying mechanisms. Next, current research on the neurobiology of OCD is examined, including work probing the role of various neurotransmitters and other endogenous processes and etiology as clues to the neurobiological fault that may underlie OCD. A new perspective on preclinical research is advanced, using the Research Domain Criteria to propose an adaptationist viewpoint that regards OCD as the dysfunction of a normal motivational system. A systems-design approach introduces the security motivation system (SMS) theory of OCD as a framework for research. Finally, a new perspective on psychopharmacological research for OCD is advanced, exploring three approaches: boosting infrastructure facilities of the brain, facilitating psychotherapeutic relearning, and targeting specific pathways of the SMS network to fix deficient SMS shut-down processes. SIGNIFICANCE STATEMENT: A significant proportion of patients with obsessive-compulsive disorder (OCD) do not achieve remission with current treatments, indicating the need for innovations in psychopharmacology for the disorder. OCD may be conceptualized as the dysfunction of a normal, special motivation system that evolved to manage the prospect of potential danger. This perspective, together with a wide-ranging review of the literature, suggests novel directions for psychopharmacological research, including boosting support systems of the brain, facilitating relearning that occurs in psychotherapy, and targeting specific pathways in the brain that provide deficient stopping processes in OCD.
100 reprints are available to download at http://pharmrev.aspetjournals.org/cgi/reprint/72/1/80.pdf?ijkey=IzJvaTV2zMR5fes&keytype=finite
... Production of NO through iNOS and inflammatory process have been implicated in both psychosis and depression (23,103). It is relevant to note that diverse antidepressants (104) and antipsychotics (105) target the NO system, while selectively targeting the NO system has been implicated in the antidepressant and antipsychotic actions of methylene blue (62,63). ...
New treatments are urgently needed for serious mental illnesses including bipolar disorder and schizophrenia. This review proposes that Garcinia mangostana Linn. (mangosteen) pericarp is a possible adjunctive therapeutic agent for these disorders. Research to date demonstrates that neurobiological properties of the mangosteen pericarp are well aligned with the current understanding of the pathophysiology of bipolar disorder and schizophrenia. Mangosteen pericarp has antioxidant, putative neuroprotective, anti-inflammatory, and putative mitochondrial enhancing properties, with animal studies demonstrating favorable pharmacotherapeutic benefits with respect to these disorders. This review summarizes evidence of its properties and supports the case for future studies to assess the utility of mangosteen pericarp as an adjunctive treatment option for mood and psychotic disorders.
... Serotonin 5 H TR1B agonists abolished NMDAR-evoked enhancement of NOS activity. Administration of ser- otonergic antidepressants decreased hippocampal nNOS activity ( Wegener et al., 2003;Luo and Tan, 2001). Interestingly, other lines of antidepressant targeting NA and DA also involved in suppression of NOS ( Krass et al., 2011;Ostadhadi et al., 2016b). ...
Affective disorders including major depressive disorder (MDD), bipolar disorder (BPD), and general anxiety affect more than 10% of population in the world. Notably, neuronal nitric oxide synthase (nNOS), a downstream signal molecule of N-methyl-D-aspartate receptors (NMDARs) activation, is abundant in many regions of the brain such as the prefrontal cortex (PFC), hippocampus, amygdala, dorsal raphe nucleus (DRN), locus coeruleus (LC), and hypothalamus, which are closely associated with the pathophysiology of affective disorders. Decreased levels of the neurotransmitters including 5-hydroxytryptamine or serotonin (5-HT), noradrenalin (NA), and dopamine (DA) as well as hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis are common pathological changes of MDD, BPD, and anxiety. Increasing data suggests that nNOS in the hippocampus play a crucial role in the etiology of MDD whereas nNOS-related dysregulation of the nitrergic system in the LC is closely associated with the pathogenesis of BPD. Moreover, hippocampal nNOS is implicated in the role of serotonin receptor 1 A (5-HTR1 A) in modulating anxiety behaviors. Augment of nNOS and its carboxy-terminal PDZ ligand (CAPON) complex mediate stress-induced anxiety and disrupting the nNOS-CAPON interaction by small molecular drug generates anxiolytic effect. To date, however, the function of nNOS in affective disorders is not well reviewed. Here, we summarize works about nNOS and its signal mechanisms implicated in the pathophysiology of affective disorders. On the basis of this review, it is suggested that future research should more fully focus on the role of nNOS in the pathomechanism and treatment of affective disorders.
... The mechanisms involved in the antidepressant-like effect of NOS inhibitors are still under investigation. In the central nervous system, NO may modulate extracellular levels of various neurotransmitters including 5-hydroxitripatamnine (5-HT), noradrenaline, dopamine and glutamate [18]. Experimental evidence has indicated that the antidepressant-like effects of nNOS inhibitors may result from a change of 5-HT levels in the brain [19,20]. ...
Clinical and experimental evidence indicates that nitric oxide (NO) is involved in the genesis of depression as well as in antidepressant drug effects. Inhibitors of nitric oxide synthases (NOS) exert antidepressant-like effect in several animal models, but also interfere with the locomotor activity. The involvement of different isoforms of NOS in the antidepressant-like effects is not clearly established. The objective of this study was to investigate the effects of acute or repeated administration of selective inhibitors of neuronal NOS (nNOS) and induced NOS (iNOS), 7 nitroindazole (7NI) and 1400 W, respectively, in mice subjected to open field (OF) and forced swim test (FST). We also investigated if the antidepressant-like effect of nNOS inhibitor, 7NI, was dependent on hippocampal serotonin. The results demonstrated that single or repeated (3 and 7 days) administration of 7NI resulted in antidepressant-like effects in mice, evidenced by a significant decrease in immobility time in the FST. However, antidepressant-like effects of the iNOS inhibitor, 1400W, were only identified after repeated administration for 3 or 7 days. The effects of both inhibitors were comparable to those obtained with the classical antidepressant fluoxetine. It was also demonstrated that the effect of 7NI was dependent of hippocampal serotonin. We concluded that inhibition of nNOS and iNOS result in antidepressant-like effects, and that these effects hold up after repeated administration.
... In rats, le Grand et al. [17] demonstrated that serotonin depletion induces cortical hyperexcitability and that this effect involves the nitric oxide pathway, suggesting a close relationship between nitric oxide and serotonin. In addition, serotonergic antidepressants decrease nitric oxide synthase activity in the rat hippocampus (Wegener et al., 2003) The present study aims to answer the following question: Does tianeptine further enhance or potentiate the effects of L-arginine treatment on CSD? To address this subject, CSD electrophysiological data were obtained from the cortex of young and adult rats that were systemically treated with arginine from postnatal day 7 to 28, and subjected to topical tianeptine treatments. ...
In the rat, we previously demonstrated that serotonin-enhancing drugs impair cortical spreading depression (CSD) and that L-arginine (arginine) treatment enhances CSD. Here, we investigated the interaction between topical application of the serotonin uptake enhancer tianeptine and systemic arginine administration on CSD. From postnatal day 7 to 28, female Wistar rats (n = 40) received by gavage 300 mg/Kg/day arginine (n = 20) or water (n = 20). Half of the arginine- or water-treated rats underwent CSD recording at 30–40 days of age (young), while the other half was recorded at 90–120 days (adult). Following baseline recording (four episodes of CSD), we applied tianeptine solution (10 mg/ml) to a rectangular portion of the intact dura mater for 10-min and then elicited CSD. This procedure was repeated three times. Compared to baseline values, CSD velocities and amplitudes following tianeptine application increased, and CSD duration decreased significantly (p < 0.05) in both young and adult rats, regardless of treatment group. CSD acceleration caused by systemic treatment with arginine is in agreement with previous findings. Topical cortical application of tianeptine replicated the effect of systemic application, suggesting a cortically based mechanism for tianeptine’s action. However, the absence of interaction between arginine and tianeptine treatments suggests that they probably act through separate mechanisms.
... The NO system has been implicated in the treatment, 22,46-54 as well as the pathobiology of depression. 49,50,[55][56][57] We, therefore, further investigated PSD-95, nNOS, CAPON and sGC-β1. PSD-95 and nNOS proteins have been shown to associate using PDZ domain-based interaction. ...
The aim of this study was to identify molecular pathways related to antidepressant response. We administered paroxetine to the DBA/2J mice for 28 days. Following the treatment, the mice were grouped into responders or non-responders depending on the time they spent immobile in the forced swim test. Hippocampal metabolomics and proteomics analyses revealed that chronic paroxetine treatment affects glutamate-related metabolite and protein levels differentially in the two groups. We found significant differences in the expression of N-methyl-d-aspartate receptor and neuronal nitric oxide synthase proteins between the two groups, without any significant alterations in the respective transcript levels. In addition, we found that chronic paroxetine treatment altered the levels of proteins associated with the ubiquitin–proteasome system (UPS). The soluble guanylate cyclase-β1, proteasome subunit α type-2 and ubiquitination levels were also affected in peripheral blood mononuclear cells from antidepressant responder and non-responder patients suffering from major depressive disorder. We submit that the glutamatergic system and UPS have a crucial role in the antidepressant treatment response in both mice and humans.
... Various classes of antidepressant, including electroconvulsive therapy, have been found to suppress glutamate-NMDA receptor activity (Stewart and Reid, 2002), purportedly by reducing the proportion of high affinity glycine sites on the NMDA receptor (Skolnick et al., 1996). Similarly, various antidepressants including IMI decrease hippocampal NOS activity as determined by microdialysis (Wegener et al., 2003). Thus, it is reasonable to assume that discontinuation of the antidepressant, in this case IMI, will rekindle previously inhibited NMDA receptor activity (Harvey et al., 2002). ...
... We also investigated the involvement of nitric oxide in the antidepressant-like effect of HEVp. These studies found that the modulation of depression depends on NOS (nitric oxide synthetase) inhibition to exert antidepressant effects in pharmacological depression models [19,35]. In addition, other studies suggest that NOS inhibition can be used as a strategy to enhance the effectiveness of antidepressants that affect other systems, such as the serotonergic system [36]. ...
Background: Previous studies carried out in our laboratories have shown that Valeriana prionophylla displays central effects in mice. The antidepressant effect of the Valeriana prionophylla was the most prominent effect. The goal of this study was to evaluate the mechanism of action of the antidepressant property of HEVp, and its effect when used chronically.Methods: Experiments were performed using the forced swimming test and the open field test. Female Swiss mice (25-30 g, 3 months) were divided into groups (N=8-10): negative control (saline), antagonist systems evaluated, HEVp and antagonist/HEVp. The treatments with NAN-190 (0.5 mg/kg, i.p.), ketanserin (5 mg/kg, i.p.), prazosin (1 mg/kg, i.p.), yohimbine (1 mg/kg, i.p.), haloperidol (0.2 mg/kg, i.p.), pimozide (0.2 mg/kg, i.p.), SCH-23390 (0.05 mg/kg, i.p.), L-arginine (750 mg/kg, i.p.), bicuculline (1 mg/kg, i.p.) and phaclofen (1 mg/kg, i.p.) were administered 30 min before HEVp. The treatments with reserpine (2 mg/kg, i.p.) and PCPA (100 mg/kg, i.p.) were administered 4 hours and 4 days before the test, respectively. Sub-chronic treatment was administered for 15 days, and the test was performed on days 1, 7 and 15 of the treatment.Results: The anti-immobility effect caused by HEVp was significantly attenuated by treatment of the reserpine, PCPA, NAN-190, ketanserin, prazosin, yohimbine, L-arginine, bicuculline and phaclofen, but was not affected by haloperidol, pimozide and SCH-23390.Conclusion: The mechanisms involved in their effects indicate that HEVp produces antidepressant effects through pathways that involve interaction with L-arginine-nitric oxide, serotonergic and GABAergic systems, as well as interaction with the α-adrenoceptors.
... Children experiencing the PTSD, usually underwent alterations in hypothalamic-pituitary-adrenal axis, catecholamine and norepinephrine, which results in pathological and detrimental brain development [5]. Interestingly, the inhibition of nitric oxide in hippocampus by antidepressant has promising outcome to alleviate the PTSD symptoms [6]. While, the augmented level of plasma nitrates in depressive patients are found to be associated with suicide attempts [7]. ...
nderstanding suicide attack is one of the highly complicated problems in the field of psychological disorders. Post-traumatic stress disorder (PTSD), may occur in individuals subjected to traumatic assaults like terrorism, warfare, sexual abuse or natural disaster. Individual's living within war affected area often develops PTSD, which may consequently leads to cognitive and memory impairment. The war induced PTSD patient, is under the influence of severe stress; terror and helplessness as it manipulate and retrieve the past trauma as a current threat. Substantial evidences support that PTSD patients are more prone to varying degree of neurological and psychological complications. In this correspondence, we wish to highlight the biological consequence of suicide attack from the perspective of war induced PTSD. Earlier research also supports that PTSD and suicide have some common basis like alterations in hypothalamic pituitary-adrenal axis, nitric oxide and catecholamine like norepinephrine and serotonin level. Thus it is important to uncover the risk of PTSD due to war on terror with precision towards suicide attack and minimize the detriment followed by it. PTSD through the development of depression, irritability and anger, is one amongst the major causes of suicide attack. In order to clarify the underlying psychological mechanism, there is a pressing need to address it from different aspects like disease causing synaptic plasticity and abnormal brain development. PTSD is a reaction to past traumatic events. For instance, the danger of perceived threat due to witness of deaths in a war, may develop a constellation of properties that may leads to PTSD. Usually, it initiates a sequence of behavioral and cognitive changes that can be anticipated to reduce the perceived threat. However, the consequences of perceived threat lead to cognitive changes and thus maintain a devastating disorder. Appraisals of such memory not only generate situational fear but also the avoidance, which leads to enhanced trepidation and over-activity. For example, a person exposed to a road side traumatic accident may avoid driving; for having an impractical faith that it may happen again, thereby affecting its social life.
... Furthermore, antidepressants used in the treatment of PTSD were suggested to decrease glutamate level and inhibit NOS. 43,[46][47][48][49][50][51] Proline, a non-essential amino acid, is synthesized from glutamate by the reversal of reactions in proline catabolism. 52 Endogenous extracellular proline is considered to increase the effects of glutamate in the synaptic cleft. ...
Objective:
Many neurochemical systems have been implicated in the development of Posttraumatic Stress Disorder (PTSD). The prolidase enzyme is a cytosolic exopeptidase that detaches proline or hydroxyproline from the carboxyl terminal position of dipeptides. Prolidase has important biological effects, and to date, its role in the etiology of PTSD has not been studied. In the present study, we aimed to evaluate prolidase activity in patients with PTSD.
Methods:
The study group consisted of patients who were diagnosed with PTSD after the earthquake that occurred in the province of Van in Turkey in 2011 (n=25); the first control group consisted of patients who experienced the earthquake but did not show PTSD symptoms (n=26) and the second control group consisted of patients who have never been exposed to a traumatic event (n=25). Prolidase activities in the patients and the control groups were determined by the ELISA method using commercial kits.
Results:
Prolidase activity in the patient group was significantly lower when compared to the control groups. Prolidase activity was also significantly lower in the traumatized healthy subjects compared to the other healthy group (p<0.01).
Conclusion:
The findings of the present study suggest that the decrease in prolidase activity may have neuroprotective effects in patients with PTSD.
... In studies measuring NO levels on cerebellar Purkinje fiber synapses in rats under depression, the authors reported that changes in NO levels were associated with psychomotor failure (48,49). One study showed that fluoxetine and tianeptine as antidepressant agents inhibit nNOS in the CNS to suppress NO activity (50). In one study where NO, nesfatin-1, and ghrelin levels were investigated in patients with major depression after venlafaxine treatment, posttreatment nesfatin-1 and ghrelin levels decreased significantly, contrary to the NO level, which increased significantly. ...
Background/aim:
We aimed to investigate and compare to healthy controls the variations in the levels of nitric oxide (NO), asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA), and L-arginine levels in patients with obsessive-compulsive disorder (OCD).
Materials and methods:
We enrolled 30 patients with OCD and 30 healthy controls in the study consecutively. Diagnostic interviews of all participants were conducted with the Structured Clinical Interview for Axis I Disorders (SCID-I), and sociodemographic data of the participants were recorded. Patients scoring 10 points or more on the Yale-Brown Obsessive-Compulsive Scale were enrolled in the study.
Results:
The NO levels of patients with OCD were increased compared to the control group, but the increase was not statistically significant (P > 0.05). However, patients with OCD had significantly lower levels of ADMA, SDMA, and L-arginine compared with the controls (P < 0.001).
Conclusion:
We found a significant decrease in ADMA, SDMA, and L-arginine as NO inhibitors between the groups, possibly because of an increase in NO. However, the insignificant increase in NO suggests that ADMA, SDMA, and L-arginine play direct and potentially important roles in OCD biology.
... Regulating the centrally generated NO is considered beneficial for managing the systemic illness including depression (Heiberg et al., 2002 ). Various NOS inhibitors were found to possess antidepressant like effect without any effect on the locomotor activity of animals (Wegener et al., 2003). These effects of NOS are dose dependent and can be inhibited by the concomitant administration of nitric oxide precursor such as l-arginine. ...
... The antidepressant effect of tianeptine is due to various CNS changes observed with its administration viz. enhanced uptake of 5-HT in cortex, hippocampus and hypothalamus [14,15], attenuation of 5-HT induced inwardly rectifying K + current resulting in increased excitability of serotoninergic neurons in dorsal raphe [16], decreased susceptibility of 5-HT to breakdown by central monoamine oxidase type A [16,17], increase in L-Noradrenaline levels through an unknown mechanism [14], rise in level of dopamine (DA) in nucleus accumbens [18], enhancement of functional responsiveness of dopaminergic D2/D3 receptors [19], blockade of 5-HT1B presynaptic heteroreceptors mediated release of acetylcholine independent of its effect on 5-HT availability [20], decrease in elevation of nitric oxide (NO, a neurotoxin) levels by inhibiting activity of NO synthase (NOS) probably due to crosstalk between 5-HT-glutamate-NO pathways [21][22]. Verapamil has been suggested to exert antidepressant effect by inhibiting 5-HT uptake by a mechanism that does not involve alteration in calcium fluxes [8,23], increasing the NA release from sympathetic neurons directly as well as by blocking pre-junctional α2 receptors [8,24] and interacting with catecholamine storage vesicles so as to reduce taking up and storing of catecholamines in them [8]. ...
... This return to normal levels has been shown for superoxide dismutase (SOD), xanthine oxidase, adenosine deaminase and NO (Herken et al., 2007). Finally, inhibitors of NO synthase (NOS) act as antidepressants (Joca and Guimarães, 2006) in a rat model of MDD, and SSRI administration inhibits NOS (Wegener et al., 2003). ...
The exact pathophysiology of major depressive disorder (MDD) remains elusive. The monoamine theory, which hypothesizes that MDD emerges as a result of dysfunctional serotonergic, dopaminergic and noradrenergic pathways, has guided the therapy of this illness for several decades. More recently, the involvement of activated immune, oxidative and nitrosative stress pathways and of decreased levels of neurotrophic factors has provided emerging insights regarding the pathophysiology of MDD, leading to integrated theories emphasizing the complex interplay of these mechanisms that could lead to neuroprogression. In this review, we propose an integrative model suggesting that T helper 17 (Th17) cells play a pivotal role in the pathophysiology of MDD through (i) microglial activation, (ii) interactions with oxidative and nitrosative stress, (iii) increases of autoantibody production and the propensity for autoimmunity, (iv) disruption of the blood-brain barrier, and (v) dysregulation of the gut mucosa and microbiota. The clinical and research implications of this model are discussed.
... This return to normal levels has been shown for superoxide dismutase (SOD), xanthine oxidase, adenosine deaminase and NO (Herken et al., 2007). Finally, inhibitors of NO synthase (NOS) act as antidepressants (Joca and Guimarães, 2006) in a rat model of MDD, and SSRI administration inhibits NOS (Wegener et al., 2003). ...
The pathophysiology of major depressive disorder (MDD) remains elusive. The monoamine theory, which hypothesizes that MDD emerges as a result of dysfunctional serotonergic, dopaminergic and noradrenergic pathways, has guided the therapy of this illness for several decades. More recently, the involvement of activated immune, oxidative and nitrosative stress pathways and of decreased levels of neurotrophic factors has provided emerging insights regarding the pathophysiology of MDD, leading to integrated theories emphasizing the complex interplay of these mechanisms that could lead to neuroprogression. In this review, we propose an integrative model suggesting that T helper 17 (Th17) cells play a pivotal role in the pathophysiology of MDD through (i) enhanced O&NS and mitochondrial dysfunction; (ii) microglial activation and excitotoxicity; (iii) increased autoimmune responses; (iv) dysregulation of the gut mucosa and microbiota; and (v) disruption of the blood-brain barrier. The clinical and research implications of this model are discussed.
... Various mechanisms underlying the mode of action of tianeptine have been proposed, including stimulation of 5-HT uptake in the cortex and hippocampus (Mocaër et al., 1988), the effects in the lung through modulation of 5-HT 3 and 5-HT 4 receptors (Lechin et al., 2004) and via the actions on hippocampal nitric oxidemediated signalling (Wegener et al., 2003). Tianeptine has also been shown to activate Calcium-Calmodulin-dependant protein kinase II (CaMKII) and protein kinase A (PKA) via the p38, p42/44 Mitogen-activated protein kinases (MAPK) and c-Jun N-terminal kinases (JNK) pathways in the hypothalamus and cortex (Szegedi et al., 2011). ...
Respiratory depression remains an important clinical problem that limits the use of opiate analgesia. Activation of AMPA glutamate receptors has been shown to reverse fentanyl-induced respiratory changes. Here, we explored whether tianeptine, a drug known for its ability to phosphorylate AMPA receptors, can be used to prevent opiate-induced respiratory depression. A model of respiratory depression in conscious rats was produced by administration of morphine (10mg/kg, i.p.). Rats were pre-treated with test compounds or control solutions 5min prior to administration of morphine. Respiratory activity was measured using whole-body plethysmography. In conscious animals, tianeptine (2 and 10mg/kg, ip) and DP-201 (2-(4-((3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2] thiazepin-11-yl)amino)butoxy)acetic acid; tianeptine analogue; 2mg/kg, ip) triggered significant (~30%) increases in baseline respiratory activity and prevented morphine-induced respiratory depression. These effects were similar to those produced by an ampakine CX-546 (15mg/kg, ip). The antinociceptive effect of morphine (hot plate test) was unaffected by tianeptine pre-treatment. In conclusion, the results of the experiments conducted in conscious rats demonstrate that systemic administration of tianeptine increases respiratory output and prevents morphine-induced respiratory depression without interfering with the antinociceptive effect of opiates.
Copyright © 2015. Published by Elsevier B.V.
... 2009). Various studies have demonstrated that depression involves an aberrant NO pathway, whereas antidepressants can target this signaling cascade in the brain (Wegener et al. 2003;Harvey et al. 2003Harvey et al. , 2006. In other studies, escitalopram significantly elevated serum SOD and CAT activity in frontal cortices of rats exposed to chronic mild stress (Shalaby and Kamal. ...
Major depression has been associated with higher levels of air pollution that in turn leads to neurodegeneration via increased oxidative stress. There is a need for suitable translational animal models to study the role of oxidative stress in depression and antidepressant action.
Considering the gene X environment hypothesis of depression, the present study investigated the effect of chronic ozone inhalation on depression and anxiety-related behavior, cognition, and brain markers of oxidative stress in the Flinders Sensitive Line (FSL) rat. In addition, response to the antioxidant melatonin, and the antidepressants desipramine or escitalopram, was assessed.
Rats were exposed to ozone (0.0 or 0.3 parts per million (ppm)) per inhalation for 4 h daily for a period of 15 days, while simultaneously receiving saline or the above-mentioned drugs.
The data indicate that chronic ozone inhalation induced memory impairment, anxiety and depression-like effects, reduced cortical and hippocampal superoxide dismutase and catalase activity, and compromised central monoamine levels similar to that noted in depression. Moreover, the behavioral and neurochemical effects of melatonin, desipramine, and escitalopram were mostly attenuated in the presence of ozone.
Thus, genetically susceptible individuals exposed to high levels of oxidative stress are at higher risk of developing mood and/or an anxiety disorders, showing greater redox imbalance and altered behavior. These animals are also more resistant to contemporary antidepressant treatment. The presented model provides robust face, construct, and predictive validity, suitable for studying neuronal oxidative stress in depression, antidepressant action and mechanisms to prevent neuronal oxidative stress.
... enhanced uptake of 5-HT in cortex, hippocampus and hypothalamus, 19,20 attenuation of 5-HT induced inwardly rectifying K + current resulting in increased excitability of serotoninergic neurons in dorsal raphe, 21 decreased susceptibility of 5-HT to breakdown by central monoamine oxidase type A, 19,22 increase in L-Noradrenaline levels through an unknown mechanism, 19 rise in level of dopamine (DA) in nucleus accumbens, 23 enhancement of functional responsiveness of dopaminergic D 2 /D 3 receptors, 24 blockade of 5-HT 1B presynaptic heteroreceptors mediated release of acetylcholine independent of its effect on 5-HT availability, 25 decrease in elevation of nitric oxide (NO, a neurotoxin) levels by inhibiting activity of NO synthase (NOS) probably due to crosstalk between 5-HT-glutamate-NO pathways. [26][27][28] Nifedipine has been suggested to exert antidepressant action by interrupting calcium-calmodulin-NOS-guanylyl cyclase signaling pathway, activation of 5-HT 1A receptors thereby reducing uptake of 5-HT, increasing intracellular calcium activity by activating 5-HT 2 and 5-HT 3 and GABA A activation on secondary inhibitory interneurons leading to release of NA. 11,[29][30][31] Antidepressant activity was enhanced when nifedipine in Phase II was combined with fl uvoxamine, venlafaxine and tianeptine compared to the effects of individual drugs when administered alone. This enhancement might be due to synergism of their antidepressant effects. ...
... Dysfunction of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) cascade is strongly linked to the neurobiology of depression (Harvey, 1996;Dhir and Kulkarni, 2011;Wegener et al., 2010;Suzuki et al., 2001). Pre-clinical studies have shown that nitric oxide synthase (NOS) inhibitors exhibit antidepressant effects (Harkin et al., 1999) while various antidepressants also suppress hippocampal NOS activity in vivo (Wegener et al., 2003). ...
Aims:
The phenothiazinium compound, methylene blue (MB), possesses diverse pharmacological actions and is attracting attention for the treatment of bipolar disorder and Alzheimer's disease. MB acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and possesses antidepressant activity in rodents. The goal of this study was to synthesise a structural analogue of MB, ethylthioninium chloride (ETC), and to evaluate the effects of the structural changes on the MAO inhibitory and antidepressant properties of MB. This study also investigated the antidepressant properties of azure B, the major metabolite of MB, versus MB and imipramine as active comparators.
Main methods:
ETC and azure B were firstly evaluated as inhibitors of human MAO, and secondly for antidepressant-like activity in the acute forced swim test (FST) in rats, and compared to saline, imipramine and MB.
Key findings:
The results document that ETC is a reversible inhibitor of MAO-A and MAO-B with IC50 values of 0.510 μM and 0.592 μM, respectively, and that it is a weaker MAO-A inhibitor than MB and azure B. ETC and azure B were more effective than imipramine and MB in reversing immobility in the FST without inducing locomotor effects, with evidence supporting a serotonergic action. Of interest is the finding that ETC is more toxic for cultured cells than MB.
Conclusion:
Azure B may therefore be a contributor to the antidepressant effect of MB. Small structural changes made to MB retain its antidepressant effect, even though the resulting phenothiazinium compound possesses reduced MAO-A inhibitory potency.
... While the interaction of these inhibitors with the nitric oxide synthase protein at the molecular level is not fully understood. The nitric oxide synthase inhibitors have been reported to possess antidepressant-like behavioural properties at doses that are without any effect on locomotor activity (Wegener et al., 2003). The neuronal isoform of nitric oxide synthase (nNOS), the enzyme responsible for the production of nitric oxide in the central nervous system, represents an attractive target for the treatment of various neurodegenerative disorders (Tylor B.S et al., 1997). ...
Nitric oxide synthase inhibitors have been regarded as beneficial for psychiatric disorders like depression. Many studies indicated that nitric oxide synthase inhibitors have antidepressant-like activity in various animal models. With the objective to design new chemical entities with enhanced inhibitory potencies against nitric oxide synthase enzyme. This study was designed to explore binding affinity and antidepressant-like activity of nitric oxide synthase inhibitor L-NAME with the nitric oxide synthase using Glide docking program and hydrogen-bonding interactions were observed between the inhibitors and the target. L-NAME docked with other nitric oxide synthase inhibitors like L-Nitro Arginine, 7-Nitro Indazole and Methylene blue on the target molecule. The energy minimized final average complex structure suggests that the Glide Extra Precision (XP) derived docked complexes are in a state of near equilibrium. The structure-based drug design strategy described in this study will be highly useful for the development of new inhibitors with high potency and selectivity. From the docking result we can conclude that L-NAME may have good binding affinity toward the nitric oxide synthase enzyme. Also L-NAME having nearly similar results with the L-Nitro Arginine which shows antidepressant like activity so from this result we can conclude that L-NAME may have antidepressant activity like L-Nitro Arginine. Abbreviation: N (G)-nitro-L-arginine methyl ester (L-NAME), L-Nitro arginine (L-NA), 7-Nitroindazole (7-NI), Neuronal nitric oxide synthase (nNOS).
Locomotor behavioral sensitization represents an animal model for understanding neuroadaptive processes related to repeated drug exposure. Repeated stress can elicit a cross-sensitization to the stimulant response of ethanol, which involves neuronal nitric oxide synthase (nNOS). Activation of N-methyl D-aspartate (NMDA) glutamate receptors triggers nNOS and the synthesis of nitric oxide (NO). In this study, we investigated the effects of blocking NMDA receptors using the NMDA receptor antagonist MK-801 on the cross-sensitization between restraint stress and ethanol. We also evaluated the nNOS activity in the prefrontal cortex (PFC) and hippocampus. Mice were pretreated with saline or MK-801 30 minutes before an injection of saline or stress exposure for 14 days. On the following day, they were challenged with either saline or 1.8 g/kg ethanol. Swiss male mice pretreated with 0.25 mg/kg MK-801 exhibited a sensitized response to ethanol. Moreover, MK-801 potentiated the cross-sensitization between stress and ethanol. However, MK-801 prevented the enhanced nNOS activity in stress-exposed groups (challenged with saline or ethanol) in the PFC; the antagonist also prevented the ethanol-induced increase in nNOS activity and reduced this enzyme activity in mice exposed to stress in the hippocampus. These data indicate that systemic treatment with the NMDA antagonist potentiated, rather than blocked, ethanol-induced behavioral sensitization and that this effect is dissociable from the capacity of NMDA antagonists reduce ethanol/stress-induced NOS stimulation in the PFC and hippocampus.
The history of Danish neuroscience starts with an account of impressive contributions made at the 17th century. Thomas Bartholin was the first Danish neuroscientist, and his disciple Nicolaus Steno became internationally one of the most prominent neuroscientists in this period. From the start, Danish neuroscience was linked to clinical disciplines. This continued in the 19th and first half of the 20th centuries with new initiatives linking basic neuroscience to clinical neurology and psychiatry in the same scientific environment. Subsequently, from the middle of the 20th century, basic neuroscience was developing rapidly within the preclinical university sector. Clinical neuroscience continued and was even reinforced during this period with important translational research and a close co-operation between basic and clinical neuroscience. To distinguish 'history' from 'present time' is not easy, as many historical events continue in present time. Therefore, we decided to consider 'History' as new major scientific developments in Denmark, which were launched before the end of the 20th century. With this aim, scientists mentioned will have been born, with a few exceptions, no later than the early 1960s. However, we often refer to more recent publications in documenting the developments of initiatives launched before the end of the last century. In addition, several scientists have moved to Denmark after the beginning of the present century, and they certainly are contributing to the present status of Danish neuroscience-but, again, this is not the History of Danish neuroscience.
The pathogenesis of mood disorders remains elusive, but it is evident that multiple factors, genetic and environmental, play a crucial role in adult psychopathology and neurobiology. Concerning therapy, a significant proportion of affective disorder patients are partial or non-responders. There has been no breakthrough in finding novel, valuable drug targets since introducing the current marketed antidepressant drugs in the 1950s to the 1980s, which all are based on monoaminergic pharmacological effects. Consequently, there is a pressing need to develop novel treatment strategies—and ultimately understand the aetiology and pathophysiology of affective disorders. Nitric Oxide serves an essential role in the nervous system. It acts as a messenger molecule in several physiological processes, including processes linked to major psychiatric diseases. The present chapter will review the general aspects of the NO system in Major depressive disorder (MDD) and focus on reducing NO production as putative therapeutic agents towards depression.
Background
Recent studies have suggested that microglial activation plays a key role in the pathogenesis of depression. In fact, neuroinflammation is associated with a phenotypic change of microglia, consisting of morphological differences, increased release of cytokines and oxidative stress products, which may contribute to the development and maintenance of depression. Antidepressants, including selective serotonin re-uptake inhibitors and serotonin–norepinephrine reuptake inhibitors, have been shown to act on the immune and oxidative stress mechanisms commonly found to be disrupted in depression. Thus, the inhibition of microglial activation may be one of the mechanisms through which they exert an antidepressant action.
Aim
This is the first review summarising in vitro and ex vivo studies investigating the effects of different classes of antidepressants on microglia activation, by examining cellular changes and/or via measuring the production of immune and/or oxidative stress signalling molecules, in microglia models of neuroinflammation with either lipopolysaccharide (LPS) or cytokines. A total of 23 studies were identified, 18 using LPS stimulation and 5 using cytokines stimulation.
Results
Overall, the studies show that antidepressants, such as selective serotonin re-uptake inhibitors, serotonin–norepinephrine reuptake inhibitors, monoamine oxidase inhibitors and tricyclic antidepressants prevented microglial activation, including reduced microglial reactivity and decreased immune and oxidative stress products, in both models. However, specific antidepressants, such as bupropion and agomelatine did not prevent interferon-gamma (IFN-γ)-induced microglial activation; and for other antidepressants, including phenelzine, venlafaxine and sertraline, the results of different studies were inconsistent.
Conclusions
Overall, results summarised in this review support the hypothesis that the action of at least certain classes of antidepressants may involve regulation of microglial activation, especially when in presence of increased levels of inflammation.
Carbamazepine, an anticonvulsant drug, has shown
antidepressant effects in clinical and experimental
models. Nitric oxide (NO) is a neurotransmitter in the
central nervous system and has been involved in a
variety of diseases including depression. In the present
study, the involvement of NO/cyclic GMP/KATP channels
pathway in the antidepressant action of carbamazepine
was investigated in mice. The antidepressant-like
activity was assessed in the forced swim test (FST)
behavioral paradigm. Carbamazepine reduced (40mg/
kg, intraperitoneal) immobility period. The antidepressant-
like effect of carbamazepine (40mg/kg, intraperitoneal)
was prevented by pretreatment with L-arginine [substrate
for NO synthase (NOS), 750mg/kg, intraperitoneal],
sildenafil (a PDE-5 inhibitor, 5mg/kg, intraperitoneal) and
diazoxide (K+
channels opener, 10mg/kg). Pretreatment
of mice with L-NAME (a non-selective NOS inhibitor,
10mg/kg, intraperitoneal), methylene blue (direct
inhibitor of both NOS and soluble guanylate cyclase,
10mg/kg, intraperitoneal) and glibenclamide (an ATP-
sensitive K+
channel blocker, 1mg/kg, intraperitoneal)
produced potentiation of the action of a sub-effective
dose of carbamazepine (30mg/kg, intraperitoneal).
Also, carbamazepine (30mg/kg) potentiated the
antidepressant-like effect of fluoxetine through NO
modulation. The various modulators used in the study
did not produce any changes in locomotor activity per se.
The results demonstrated that the antidepressant-like
effect of carbamazepine in the FST involved an interaction
with the NO/cGMP/KATP channels pathway.
Carnitine serves an important role in the burning of fat for energy, and ferrying fatty acids across the walls of the mitochondria, where they are oxidized and turned into energy. Carnitine's role in fat metabolism leads it to affect, in some degree, all the other energy metabolism in the cell, including the burning of carbohydrate. In this way it can be linked to glucose metabolism, insulin and Metabolic Syndrome. There is compelling evidence that 1.5–3 g a day of acetyl-carnitine can improve cognitive function of individuals in the milder, early stages of Alzheimer's disease. Acetylcholine levels are decreased in many forms of dementia, and most of the drugs used for treatment of Alzheimer's disease increase the availability of acetylcholine by preventing its enzymatic destruction in the brain. Carnosine is useful in helping prevent damage caused by too much sugar in the body. Sugars, such as glucose or fructose, can bind with proteins. This binding not only damages the protein, but the glycosylated protein can stimulate secondary inflammatory processes. Increasing levels of carnosine in the brain may have a protective effect from Alzheimer's disease. Consumption of chocolate tends to inhibit synthesis of leukotrienes. Leukotrienes act to constrict blood vessels, promote inflammation, and activate platelets. There are many other nutritional supplements that play an important role in Metabolic Syndrome.
Studies about the pathogenesis of mood disorders have consistently shown that multiple factors, including genetic and environmental, play a crucial role on their development and neurobiology. Multiple pathological theories have been proposed, of which several ultimately affects or is a consequence of dysfunction in brain neuroplasticity and homeostatic mechanisms. However, current clinical available pharmacological intervention, which is predominantly monoamine-based, suffers from a partial and lacking response even after weeks of continuous treatment. These issues raise the need for better understanding of aetiologies and brain abnormalities in depression, as well as developing novel treatment strategies. Nitric oxide (NO) is a gaseous unconventional neurotransmitter, which regulates and governs several important physiological functions in the central nervous system, including processes, which can be associated with the development of mood disorders. This review will present general aspects of the NO
system in depression, highlighting potential targets that may be utilized and further explored as novel therapeutic targets in the future pharmacotherapy of depression. In particular, the review will link the importance of neuroplasticity mechanisms governed by NO to a possible molecular basis for the antidepressant effects.
Mood disorders are chronic, recurrent mental diseases that affect millions of individuals worldwide. Although over the past 40 years the biogenic amine models have provided meaningful links with the clinical phenomena of, and the pharmacological treatments currently employed in, mood disorders, there is still a need to examine the contribution of other systems to the neurobiology and treatment of mood disorders. This article reviews the current literature describing the potential role of nitric oxide (NO) signaling in the pathophysiology and thereby the treatment of mood disorders. The hypothesis has arisen from several observations including (i) altered NO levels in patients with mood disorders; (ii) antidepressant effects of NO signaling blockers in both clinical and pre-clinical studies; (iii) interaction between conventional antidepressants/mood stabilizers and NO signaling modulators in several biochemical and behavioral studies; (iv) biochemical and physiological evidence of interaction between monoaminergic (serotonin, noradrenaline, and dopamine) system and NO signaling; (v) interaction between neurotrophic factors and NO signaling in mood regulation and neuroprotection; and finally (vi) a crucial role for NO signaling in the inflammatory processes involved in pathophysiology of mood disorders. These accumulating lines of evidence have provided a new insight into novel approaches for the treatment of mood disorders.
The pathogenesis of mood disorders remains elusive, but it is evident that multiple factors, genetic and environmental, play a crucial role for adult psychopathology and neurobiology. With regard to therapy, a significant proportion of affective disorder patients are partial or nonresponders, and there has been no major breakthrough in finding novel effective drug targets since the introduction of the current marketed antidepressant drugs in the 1950s to the 1980s, which all are based on monoaminergic pharmacological effects. Consequently, there exists a pressing need to develop novel treatment strategies – and ultimately understand the etiology and pathophysiology of affective disorders.
Nitric oxide serves an important role in the nervous system, where it acts as a messenger molecule in a number of physiological processes, including processes being linked to the major psychiatric diseases. This chapter will review general aspects of the NO system in major depressive disorder (MDD), as well as focus on the inhibition of NO production as putative therapeutic agents toward depression.
Depression has become a common illness among individuals of every age group. Among numerous factors held responsible for depression stress is most vital. Behind the specified disorder various hypothesis has been laid out where Nitric Oxide is emerging target to treat stress induced depression. Antidepressant potential of piperine in stressed and unstressed condition was evaluated using tail suspension test and forced swim test whereas locomotor activity was evaluated by actophotometer. Results of the present study indicate the potential of antidepressant effect of piperine in stress. Methylene blue potentiated the effect of sub- effective dose of PP and SB-203580 enhanced effect of Piperine in stressed mice with no array on locomotor activity with direct influence on Nitric oxide. Piperine produced significant changes in Nitric oxide level which is pathophysiologic mediator(s) of depression, which validate the action of piperine on depression symptoms.
Context:
Wuling mycelia powder is the dry powder of rare a fungi Xyla ria sp., Carbon species, with a long history of medicinal use in Chinese medicine. Recently it has shown a powerful antidepressant activity in clinic.
Objective:
The present study explores the antidepressant activity of Wuling mycelia powder in chronic unpredictable mild stress (CUMS) rats and its possible involvement of l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway.
Materials and methods:
Experiments were performed in the rat CUMS model. CUMS rats were treated with Wuling mycelia powder (0.5, 1.0 or 2.0 g/kg, i.g.) to test behavioral changes including the sucrose preference, the crossing number and food consumption. Further, L-arginine (substrate for nitric oxide) (750 mg/kg), 7-nitroindazole (a specific neuronal nitric oxide synthase inhibitor) (25 mg/kg), sildenafil (phosphodiesterase 5 inhibitor) (5 mg/kg) and methylene blue (direct inhibitor of both nitric oxide synthase and soluble guanylate cyclase) (10 mg/kg) were treated for 60 min before each test to detect the possible mechanism of antidepressant-like effect of Wuling mycelia powder.
Results:
After 4 weeks of administration, both 1.0 or 2.0 g/kg Wuling mycelia powder suppressed the behavioral changes including the sucrose preference [F(3, 31)=50.87, p<0.001], the crossing number [F(3, 31)=68.98, p<0.05], and food consumption [F(3, 31)=19.04, p<0.05] in the CUMS rats. The antidepressant-like effect of Wuling mycelia powder was prevented by pretreatment with l-arginine and sildenafil. Pretreatment of rats with 7-nitroindazole and methylene blue potentiated the effect of Wulin mycelia powder.
Discussion and conclusion:
Our findings demonstrate that Wuling mycelia powder has an antidepressant-like effect in the CUMS rats, and possible involvement of L-arginine-nitric oxide-cyclic GMP signaling pathway in its antidepressant effect.
In view of the reports that nitric oxide modulates the neurotransmitters implicated in obsessive-compulsive disorder (OCD), patients with OCD exhibit higher plasma nitrate levels, and drugs useful in OCD influence nitric oxide. Agmatine is a polyamine and widely distributed in mammalian brain which interacts with nitrergic systems. Hence, the present study was carried out to understand the involvement of nitrergic systems in the anticompulsive-like effect of agmatine. We used marble-burying behaviour (MBB) of mice as the animal model of OCD, and nitric oxide levels in hippocampus (HC) and cortex homogenate were measured. Results revealed that, agmatine (20 and 40mg/kg, i.p) significantly inhibited the MBB. Intraperitoneal administration of nitric oxide enhancers viz. nitric oxide precursor-l-arginine (l-ARG) (400mg/kg and 800mg/kg) increased MBB as well as brain nitrites levels, whereas treatment with N(G)-nitro-l-arginine methyl ester (l-NAME) neuronal nitric oxide synthase inhibitor (30mg/kg and 50mg/kg, i.p.) and 7-nitroindazole (7-NI) (20mg/kg and 40mg/kg) attenuated MBB and nitrites levels in brain. Further, in combination studies, the anticompulsive-like effect of agmatine (20mg/kg, ip) was exacerbated by prior administration of l-ARG (400mg/kg) and conversely l-NAME (15mg/kg) or 7-NI (10.0mg/kg) attenuated OCD-like behaviour with HC and cortex changes in the levels of NO. None of the above treatment had any significant influence on locomotor activity. In conclusion, Agmatine is effective in ameliorating the compulsive-like behaviour in mice which appears to be related to nitric oxide in brain.
Since the first report that the mechanism of action of antidepressants involves the facilitation of monoaminergic neurotransmission in the brain in the 1960s, the leading hypothesis about the neurobiology of depression has been the so called "monoaminergic hypothesis". However, a growing body of evidence from the last two decades also supports important involvement of non-monoaminergic mechanisms in the neurobiology of depression and antidepressant action. The discovery of nitric oxide (NO) and endocannabinoid signaling in the brain during the 1990s challenged the well-established criteria of classical neurotransmission. These transmitters are synthesized and released on demand by the post-synaptic neurons, and may act as a retrograde messenger on the presynaptic terminal, modulating neurotransmitter release. These unconventional signaling mechanisms and the important role as neural messengers have classified NO and endocannabinoids as atypical neurotransmitters. They are able to modulate neural signaling mediated by the main conventional neurotransmitters systems in the brain, including the monoaminergic, glutamatergic and GABAergic signaling systems. This review aims at discussing the fundamental aspects of NO- and endocannabinoid-mediated signaling in the brain, and how they can be related to the neurobiology of depression. Both preclinical and clinical evidence supporting the involvement of these atypical neurotransmitters in the neurobiology of depression, and in the antidepressant effects are presented here. The evidence is discussed on basis of their ability to modulate different neurotransmitter systems in the brain, including monoaminergic and glutamatergic ones. A better comprehension of NO and endocannabinoid signaling mechanisms in the neurobiology depression could provide new avenues for the development of novel non-monoamine based antidepressants.
Olfactory bulbectomy (OB) is an animal model of depression that can mimic symptoms that are characteristic of depressive patients, such as behavioral, neurochemical and neuromorphological changes. Quercetin decreased the immobility time in the forced swimming test and tail suspension test. With the open field test, quercetin did not alter the locomotor activity of mice and in the splash test, quercetin increased the time spent grooming. The repeated treatment with quercetin (25mg/kg, for 14days) reversed the behavioral hyperactivity induced by OB in the open field test and was able to prevent depressant-like effects in the forced swimming test and tail suspension test. Regarding oxidative stress, OB reduced the levels of glutathione and increase the activity of superoxide dismutase and lipid hydroperoxide content (LOOH) in the hippocampus. Only the increase in LOOH levels was reversed by treatment with quercetin. In a further series of experiments with non-bulbectomized mice, the antidepressant effect of quercetin in the tail suspension test was reversed by the pretreatment of mice with NMDA, l-arginine or sildenafil. The administration of methylene blue and 7-nitroindazole, in combination with an underactive dose of quercetin (5mg/kg, p.o.), decreased the immobility time in the tail suspension test compared with the use of drug alone. There was no significant change in locomotor activity in the open field test. Our results suggest that the antidepressant effect of quercetin is dependent on the inhibition of the NMDA receptors and/or synthesis of nitric oxide. In addition, considering the reduction of LOOH levels on the hippocampus, we verify that the antioxidant effects of quercetin also contribute to its antidepressive potential. These data contribute to the understanding of the mechanisms involved in the antidepressant effect of quercetin and reinforce the involvement of the NMDA receptors and the nitric oxide on the pathophysiology of depression.
Chronic ethanol administration affects many organ systems, including sexual organs. One of these organs is the vas deferens whose contractility can also be altered by selective serotonin re-uptake inhibitors (SSRIs). The aim of the present study, is to evaluate whether paroxetine (PX), a SSRI, can modify the contractile responses of isolated vas deferens obtained from rats chronically treated with ethanol to the contractile agents, potassium chloride (KCl) and adenosine triphosphate (ATP). For 21 days, alcohol was applied with a modified liquid diet to sexually mature male Sprague–Dawley rats (200–240 g). The vas deferens of the rats were excised at the end of day 21 and suspended in the organ baths by classical pharmacological methods. The responses to contractile agents tested were decreased by chronic ethanol treatment in all groups compared to their untreated matches. PX (10−7 and 10−6 M) potentiated the contractions to KCl (20–180 mM) and ATP (10−6 to 10−3 M) in epididymal portion but its higher concentrations (10−5 and 10−4 M) inhibited the responses, both in the control and chronically ethanol treated rat groups. Prazosin (PR), an alpha adrenergic receptor blocker, could not inhibit PX-induced potentiation in lower concentrations of KCl but could inhibit the potentiation occurred at higher concentrations of KCl in epididymal portion both in the control and chronically ethanol treated rat groups. PR also inhibited PX-induced potentiation on the responses to ATP in epididymal portion both in the control and chronically ethanol treated rat groups. In conclusion, all the results obtained in this study, suggest that chronic ethanol treatment decreased the contractility of vas deferens but did not alter the action pattern of PX on responses to KCl and ATP in rat vas deferens. On the other hand, the potentiation of responses to contractile agents induced by PX can be partially considered as the result of inhibition of noradrenaline re-uptake.
Many antidepressants inhibit 5-hydroxytryptamine (5HT) transport resulting in increased 5HT levels in the synapse. However, physiological regulation of neurotransmitter uptake has not been demonstrated. We have examined the effect of receptor-activated second messengers on the 5HT transporter in rat basophilic leukemia cells (RBL 2H3). Here, we show that activation of an A(3) adenosine receptor results in an increase of 5HT uptake in RBL cells, due to an increase in maximum velocity (V-max). The A(3) adenosine receptor-stimulated increase in transport is blocked by inhibitors of nitric oxide synthase and by a cGMP dependent kinase inhibitor. In fact, compounds that generate nitric oxide (NO) and the cGMP analog 8-bromo-cGMP mimicked the effect of A(3) receptor stimulation, suggesting that the elevation in transport occurs through the generation of the gaseous second messenger NO and a subsequent elevation in cGMP. Additionally, the 5HT transporter is differentially regulated by second messengers since direct activation of protein kinase C by phorbol esters decreases 5HT uptake by decreasing V-max. Our results suggest that the changes in transport are due to a direct modification of the 5HT transporter, possibly by phosphorylation, which appears to alter the rate at which transport occurs. As the 5HT transporter in RBL cells is identical to that in neurons, our results suggest that analogous mechanisms may operate in the brain.
Nitric oxide, which mediates influences of numerous neurotransmitters and modulators on vascular smooth muscle and leukocytes, can be formed in the brain from arginine by an enzymatic activity that stoichiometrically generates citrulline. We show that glutamate and related amino acids, such as N-methyl-D-aspartate, markedly stimulate arginine--citrulline transformation in cerebellar slices stoichiometrically with enhancement of cGMP levels. N omega-monomethyl-L-arginine blocks the augmentation both of citrulline and cGMP with identical potencies. Arginine competitively reverses both effects of N omega-monomethyl-L-arginine with the same potencies. Hemoglobin, which complexes nitric oxide, prevents the stimulation by N-methyl-D-aspartate of cGMP levels, and superoxide dismutase, which elevates nitric oxide levels, increases cGMP formation. These data establish that nitric oxide mediates the stimulation by glutamate of cGMP formation.
Many antidepressants inhibit 5-hydroxytryptamine (5HT) transport resulting in increased 5HT levels in the synapse. However, physiological regulation of neurotransmitter uptake has not been demonstrated. We have examined the effect of receptor-activated second messengers on the 5HT transporter in rat basophilic leukemia cells (RBL 2H3). Here, we show that activation of an A3 adenosine receptor results in an increase of 5HT uptake in RBL cells, due to an increase in maximum velocity (Vmax). The A3 adenosine receptor-stimulated increase in transport is blocked by inhibitors of nitric oxide synthase and by a cGMP-dependent kinase inhibitor. In fact, compounds that generate nitric oxide (NO) and the cGMP analog 8-bromo-cGMP mimicked the effect of A3 receptor stimulation, suggesting that the elevation in transport occurs through the generation of the gaseous second messenger NO and a subsequent elevation in cGMP. Additionally, the 5HT transporter is differentially regulated by second messengers since direct activation of protein kinase C by phorbol esters decreases 5HT uptake by decreasing Vmax. Our results suggest that the changes in transport are due to a direct modification of the 5HT transporter, possibly by phosphorylation, which appears to alter the rate at which transport occurs. As the 5HT transporter in RBL cells is identical to that in neurons, our results suggest that analogous mechanisms may operate in the brain.
Extracellular levels of serotonin (5-HT) and the regulation of 5-HT release by the 5-HT1A receptor were examined after single and repeated treatment with different types of antidepressant drugs: the selective 5-HT uptake inhibitor fluoxetine, the selective norepinephrine uptake inhibitor desipramine and the 5-HT2A/2C/alpha 2 receptor antagonist mianserin (each at 15.0 mg/kg). Extracellular levels of 5-HT were measured using in vivo microdialysis in the striatum and hippocampus of rats anesthetized with chloral hydrate. Acute administration of fluoxetine transiently elevated the levels of 5-HT in the striatum and hippocampus; desipramine did not change 5-HT levels, and mianserin slightly decreased 5-HT levels in the hippocampus. Rats were administered these antidepressant drugs for either 1 or 14 days and studied 48 hr after the final injection. Repeated treatment with fluoxetine increased base-line levels of 5-HT in the striatum and hippocampus; repeated treatment with desipramine increased base-line 5-HT levels in the striatum only, and repeated treatment with mianserin did not alter base-line 5-HT levels. Repeated fluoxetine treatment attenuated the ability of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to decrease 5-HT release in both the striatum and hippocampus. Repeated desipramine treatment did not significantly alter the effects of 8-OH-DPAT on 5-HT release, but there was a hint of a decreased effect in the hippocampus. Repeated mianserin treatment did not significantly alter the effects of 8-OH-DPAT on 5-HT release, but there was a hint of an increased effect in the striatum. The results of the present study suggest that repeated treatment with antidepressant drugs alters extracellular levels of 5-HT and the ability of 5-HT1A receptors to regulate the release of 5-HT in a regionally selective manner. These changes in the regulation of 5-HT release produced by antidepressant drugs may be associated with their therapeutic effects, because they are caused by repeated rather than acute treatment.
Chronic (14 day) but not acute (1 day) treatment of mice with clinically active antidepressants produces a significant (approximately 1.8-4.3 fold) reduction in the potency of glycine to inhibit [3H]-5,7-dichlorkynurenic acid (5,7-DCKA) binding to strychnine-insensitive glycine receptors in neocortical membranes. Moreover, these effects were not observed following chronic treatment with a variety of nonantidepressant drugs such as D-deprenyl, chlorpromazine, salbutamol, scopolamine and chlordiazepoxide. The time course and dose-response relationships for this effect were examined after treatment with two representative antidepressant drugs (imipramine and citalopram) and electriconvulsive shock (ECS). Increases in the IC50 of glycine to inhibit [3H]-5,7-DCKA binding were observed after treatment for 7 days with ECS, 10 days with citalopram and 14 days with imipramine, respectively, and were no longer apparent by the 10th day after cessation of treatment. These findings indicate that the antidepressant-induced reduction in the IC50 of glycine to inhibit [3H]-5,7-DCKA binding is: 1) a slowly developing, adaptive phenomenon; 2) remarkably persistent after cessation of treatment; and 3) a significantly better predictor of antidepressant activity (22 of 23 drugs) than either beta adrenoceptor down-regulation (15 of 23 drugs) or efficacy in the forced swim test (13 of 23 drugs) [P < .01 vs. each measure, Fisher's Exact Test]. The ability of antidepressants drawn from every principal therapeutic class to effect adaptive changes in the N-methyl-D-aspartate receptor complex is consistent with the hypothesis that this ligand-gated ion channel serves as a final common pathway of antidepressant action and indicates that glutamatergic pathways may be involved in the pathophysiology of depression.
NMDA antagonists mimic the effects of clinically effective antidepressants in both preclinical tests predictive of antidepressant action and procedures designed to model aspects of depressive symptomatology. These findings led to experiments demonstrating that chronic administration of NMDA antagonists to rodents results in a downregulation of cortical beta-adrenoceptors, a phenomenon also observed following chronic treatment with many antidepressants. These neurochemical and behavioral similarities between antidepressants and NMDA antagonists prompted us to examine the impact of chronic antidepressant treatment on NMDA receptors. Chronic (14 days) but not acute (1 day) administration of seventeen different antidepressants to mice produced adaptive changes in radioligand binding to NMDA receptors. Detailed studies with three antidepressants (imipramine, citalopram, and electroconvulsive shock) show that these changes develop slowly, persist for some time after cessation of treatment, and (for imipramine and citalopram) are dose dependent. Moreover, following chronic treatment with imipramine, these changes in radioligand binding to NMDA receptors appear restricted to the cerebral cortex. Based on the consistency of these effects across antidepressant treatments, we propose that adaptive changes in NMDA receptors may be the final common pathway for antidepressant action. The recent demonstration (Nowak et al., 1995) that radioligand binding to NMDA receptors is altered in frontal cortex of suicide victims (compared to age and post-mortem interval matched controls) is consistent with the hypothesis (Trullas and Skolnick, 1990) that this family of ligand gated ion channels is involved in the pathophysiology of depression.
Nitric oxide (NO) is a widespread and multifunctional biological messenger molecule. It mediates vasodilation of blood vessels, host defence against infectious agents and tumors, and neurotransmission of the central and peripheral nervous systems. In the nervous system, NO is generated by three nitric oxide synthase (NOS) isoforms (neuronal, endothelial and immunologic NOS). Endothelial NOS and neuronal NOS are constitutively expressed and activated by elevated intracellular calcium, whereas immunologic NOS is inducible with new RNA and protein synthesis upon immune stimulation. Neuronal NOS can be transcriptionally induced under conditions such as neuronal development and injury. NO may play a role not only in physiologic neuronal functions such as neurotransmitter release, neural development, regeneration, synaptic plasticity and regulation of gene expression but also in a variety of neurological disorders in which excessive production of NO leads to neural injury.
The aim of the present study was to investigate whether changes in brain 5-HT concentrations affect the expression of BDNF mRNA in rat brain. Brain 5-HT concentration in the rat was elevated by combined treatment with tranylcypromine and L-tryptophan, tranylcypromine alone, by a single dose of the 5-HT releasing agent p-chloroamphetamine (PCA) or by the selective 5-HT reuptake inhibitor paroxetine. 5-HT was depleted by either multiple p-chlorophenylalanine (pCPA) or PCA injections. The extent of 5-HT depletion following pCPA or PCA was monitored using 5-HT immunocytochemistry. BDNF mRNA abundance in treated rats and the corresponding vehicle injected control rats was studied by in situ hybridization histochemistry (ISHH). Two hours after the combined administration of tranylcypromine and L-tryptophan BDNF mRNA abundance in the dentate gyrus was significantly decreased but increased in the frontal cortex. Tranylcypromine alone or a single injection of PCA had similar effects on BDNF mRNA expression to the combination of tranylcypromine and L-tryptophan, i.e. they caused significant reductions of BDNF mRNA expression in dentate gyrus and increased it in frontal cortex. Paroxetine also reduced BDNF mRNA in DG but was without effect in frontal cortex. Multiple injections of both pCPA or PCA resulted in marked reductions of 5-HT immunoreactive axons in the hippocampus, pCPA being more effective. Both drugs significantly increased BDNF mRNA abundances in the dentate gyrus. Multiple PCA injections also increased BDNF mRNA expression in parietal cortex, while pCPA induced 5-HT depletion was ineffective. These results suggests that 5-HT modulates BDNF mRNA levels in rat brain.
Glutamatergic mechanisms are powerful activators of thel-arginine-nitric oxide (NO) pathway in the central nervous system (CNS). While these mechanisms have been implicated in a variety of neurodegenerative disorders, as well as psychiatric disorders such as schizophrenia and anxiety, a possible role in affective disorders has not been defined. Low gamma-hydroxy butyric acid (GABA)/high glutamate ratios appear to be aetiological factors in the syndrome of depression. In addition to effects on biogenic amines, typical antidepressants exhibit both glutamate-modulating actions and GABA enhancing properties, whileN-methyl-d-aspartate (NMDA)-receptor antagonists, similarly, display antidepressant efficacy. Excessive activation of glutamatergic/nitrergic mechanisms, leading to limbic and subcortical kindling and the synthesis of specific immediate early genes (IEG) and retrograde messengers such as NO, allow the formation of memory traces which can either predict remission of dysphoric mood or, alternatively, the development of relapse and treatment refractoriness. In parallel to its ability to induce refractoriness, lithium can augment glutamate responses, is proconvulsant, regulates gene expression and has distinct effects on NO and cGMP. These effects, including refractoriness, may be overcome with anticonvulsant/GABA-agonists or an NMDA antagonist. Not only are anti-glutamatergic or GABA-enhancing mechanisms thus vital for successful remission of depression, they may also regulate homeostatic mechanisms preventing dysphoric mood recurrence. The diverse effects of NO and cGMP on subcellular events, the unique physico-chemical properties of NO and its involvement in cellular memory processes and synaptic plasticity makes it an ideal regulator of short- and long-term adaptive changes associated with mood regulation.
Repeated 6-h daily restraint stress over 21 days reduces length and number of branch points of hippocampal CA3c pyramidal dendrites in the hippocampal formation of adult male rats. This effect is mimicked by daily injections of 40 mg/kg corticosterone. Daily treatment with tianeptine (15 mg/kg) prior to stress sessions or the corticosterone treatment prevented these effects of stress or corticosterone, respectively. Tianeptine treatment did not prevent the effects of stress to increase adrenal/body weight ratio, nor did it prevent the effects of stress to decrease body weight gain, indicating that its actions are not mediated solely by effects on stress-induced secretion of corticosterone. Because tianeptine is known to enhance neural uptake of serotonin, these results suggest that the serotonergic system may be involved in modulating stress and corticosterone effects on dendritic morphology.
The involvement of nitrergic mechanisms in the behavioural effects of diazepam in rats was studied in the elevated plus-maze, open-field and rotarod tests. Administration of the nitric oxide (NO) precursor l-arginine (100 mg/kg, i.p.), assumed to increase the synthesis of NO, abolished the anxiolytic-like effect of diazepam (2 mg/kg, i.p.) in the elevated plus-maze, whereas the inactive enantiomer d-arginine (100 mg/kg) did not. Neither diazepam alone nor in combination with l- or d-arginine affected the exploratory activity of animals in the open field. Pretreatment with l-arginine (100 and 200 mg/kg) did not modify the motor impairment of rats after diazepam (3 mg/kg) in the rotarod test. Diazepam (2 mg/kg i.p.) did not inhibit the cortical or hippocampal cytosolic NO synthase activity measured ex vivo by []l-arginine assay. Diazepam was similarly ineffective in in vitro studies at concentrations up to 10 μM. We conclude that a suppression of NO synthase activity may be important in the anxiolytic-like effect of benzodiazepines. However, diazepam does not inhibit NO synthase directly, but may affect NO synthase activity indirectly via some unknown mechanism.
In situ hybridization histochemistry and quantitative autoradiography were used to evaluate the effects of repeated administration of the serotonin reuptake enhancer, tianeptine. Tianeptine (10 mg/kg twice daily, for 14 days) significantly reduced both the expression of serotonin transporter mRNA and serotonin transporter binding sites labeled by [3H]paraxetine in rat dorsal raphe nucleus. In median raphe nucleus, tianeptine did not change either expression of serotonin transporter mRNA or binding. This effect, which is similar to a reported effect for serotonin reuptake inhibitors, may help to explain the antidepressant effect of tianeptine.
Notions of what constitutes a neurotransmitter have changed markedly with the advent in the past decade of synaptic molecules, which satisfy key neurotransmitter criteria but differ radically from classical transmitters. Thus, NO and carbon monoxide are neither stored in synaptic vesicles nor released by exocytosis. These gases do not act via traditional receptors on postsynaptic membranes. In addition, zinc, stored together with glutamate in synaptic vesicles, appears to act as an ‘antagonist’ co-transmitter at the NMDA receptor, and although localized exclusively to glia, d-serine fulfills most neurotransmitter criteria as an endogenous ligand for the ‘glycine’ site of NMDA receptors.
Immobilization stress decreases the expression of BDNF mRNA in the rat hippocampus, and this effect could contribute to the atrophy of hippocampal neurons. This study examines the influence of selective 5-HT, as well as norepinephrine, receptor antagonists on the stress-induced down-regulation of BDNF mRNA. Pretreatment with a selective 5-HT2A receptor antagonist, MDL100,907, significantly blocked the influence of stress on expression of BDNF mRNA. In contrast, pretreatment with either a selective 5-HT2C or 5-HT1A receptor antagonist did not influence the stress-induced decrease in levels of BDNF mRNA. The stress-induced decrease was also not influenced by pretreatment with antagonists of β1/2- or α1-adrenergic, or CRF-R1 receptors. The results demonstrate that 5-HT2A receptors mediate, at least in part, the stress-induced down-regulation of BDNF expression in the rat hippocampus.
The discovery of the intercellular messenger nitric oxide (NO) stimulated new concepts of how synaptic plasticity could be induced in the nervous system. While initial reports found evidence that NO is of importance for the formation of long-term potentiation of synaptic transmission (LTP) and spatial learning in rats, later reports failed to confirm these results. Novel approaches such as deletion of the gene that encodes NO synthase in mice showed that the neuronal and the endothelial isoforms are expressed in neurones. Deletion of both isoforms reduced the inducibility of LTP. Furthermore, novel selective inhibitors of NO synthase impaired spatial learning. These results support the hypothesis that NO plays an important role in synaptic transmission and explain some but not all previously contradictory results.
Using radioligand binding assays, we determined the equilibrium dissociation constants (KD's) for 37 antidepressants, three of their metabolites (desmethylcitalopram, desmethylsertraline, and norfluoxetine), some mood stabilizers, and assorted other compounds (some antiepileptics, Ca2+ channel antagonists, benzodiazepines, psychostimulants, antihistamines, and monoamines) for the human serotonin, norepinephrine, and dopamine transporters. Among the compounds that we tested, mazindol was the most potent at the human norepinephrine and dopamine transporters with KD's of 0.45 +/- 0.03 nM and 8.1 +/- 0.4 nM, respectively. Sertraline (KD = 25 +/- 2 nM) and nomifensine (56 +/- 3 nM) were the two most potent antidepressants at the human dopamine transporter. We showed significant correlations for antidepressant affinities at binding to serotonin (R = 0.93), norepinephrine (R = 0.97), and dopamine (R = 0.87) transporters in comparison to their respective values for inhibiting uptake of monoamines into rat brain synaptosomes. These data are useful in predicting some possible adverse effects and drug-drug interactions of antidepressants and related compounds.
Recent reports indicate that induction of nitric oxide (NO) evokes dopamine (DA) release from the striatum in vitro. In this study, we used L-arginine (L-Arg) to demonstrate the in vivo stimulation of DA release from the striatum of Mongolian gerbils using microdialysis. The content of DA in the striatal extracellular fluid (ECF) increased 7-15-fold in the presence of L-Arg in the perfusate as compared with that of the controls (DA level in drug-free perfusate varied from 0.050 +/- 0.009 to 0.092 +/- 0.023 pmol 10 microliters-1). Simultaneous perfusion of L-Arg with nitro-L-arginine (NLA), an inhibitor of nitric oxide synthase, markedly reduced the L-Arg effect on DA release from the striatum. The NLA-perfused animals contained DA levels significantly lower than those observed in the control striatal dialysate. These findings indicate for the first time that DA release in vivo can be induced by L-Arg, the precursor of NO. The data strongly suggest that NO may modulate striatal DA release.
In the vascular system, endothelium-derived relaxing factor (EDRF) is the name of the local hormone released from endothelial cells in response to vasodilators such as acetylcholine, bradykinin and histamine. It diffuses into underlying smooth muscle where it causes relaxation by activating guanylate cyclase, so producing a rise in cyclic GMP levels. It has been known for many years that in the central nervous system (CNS) the excitatory neurotransmitter glutamate can elicit large increases in cGMP levels, particularly in the cerebellum where the turnover rate of cGMP is low. Recent evidence indicates that cell-cell interactions are involved in this response. We report here that by acting on NMDA (N-methyl-D-aspartate) receptors on cerebellar cells, glutamate induces the release of a diffusible messenger with strikingly similar properties to EDRF. This messenger is released in a Ca2+-dependent manner and its activity accounts for the cGMP responses that take place following NMDA receptor activation. In the CNS, EDRF may link activation of postsynaptic NMDA receptors to functional modifications in neighbouring presynaptic terminals and glial cells.
In an open, clinical trial comprising a total of 21 depressed in-patients (6 men and 15 women) citalopram was administered in doses of 20-60 mg once daily for a period of at least 3 weeks. Fourteen of the patients were treated for 4 weeks, and 6 of these patients were treated for another 2 weeks. The CPRS subscale for depression (MADRS) and a global evaluation were used for assessment of the therapeutic effect. Twelve patients showed complete or partial response to treatment, and generally onset of therapeutic effect was seen within the first 2 weeks of treatment. Side-effects were generally few and mild, anxiety being the most frequent one. No pathological laboratory values were recorded, and apart from one case of slight and transient bradycardia no changes were observed in the cardiovascular parameters. Determination of plasma levels in 16 of the patients under presumed steady-state conditions showed an inter-individual variation between 28 and 616 nM/l for citalopram and between 32 and 338 nM/l for its monodemethylated metabolite for daily citalopram doses of 30-60 mg. The average ratio citalopram-desmethyl citalopram was 1.70. No correlation was found between clinical response and the plasma levels.
Many traditional statistical approaches to data analysis assume a relatively simple situation in which the investigator is testing a single hypothesis. Most research in psychiatry, on the other hand, is exploratory in nature and involves testing many hypotheses. Exploratory research presents special problems in data analysis, which are discussed in this overview. Special statistical approaches that are available to reduce error risk, such as the Bonferroni inequality, are described. The importance of selecting confidence levels appropriate to a particularly investigation, rather than arbitrary use of the .05 level, is also discussed.
In addition to its role in blood vessel and macrophage function, nitric oxide (NO) is a neurotransmitter found in high densities in emotion-regulating brain regions. Mice with targeted disruption of neuronal NO synthase (nNOS) display grossly normal appearance, locomotor activity, breeding, long-term potentiation and long-term depression. The nNOS- mice are resistant to neural stroke damage following middle cerebral artery ligation. Although CO2-induced cerebral vasodilatation in wild-type mice is NO-dependent, in nNOS- mice this vasodilation is unaffected by NOS inhibitors. Establishing a behavioural role for NO has, until now, not been feasible, as NOS inhibitor drugs can only be administered acutely and because their pronounced effects on blood pressure and other body functions obfuscate behavioural interpretations. We now report a large increase in aggressive behaviour and excess, inappropriate sexual behaviour in nNOS- mice.
The effects of intracerebral perfusion of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) and the nitric oxide synthase inhibitor N-nitroarginine (NARG) on the extracellular concentrations of glutamate (GLU) and gamma-aminobutyric acid (GABA) in striatum and CA1 area of the hippocampus were studied. Continuous push-pull perfusions at a flow rate of 20 microliters min-1 were performed in the conscious rat. SIN-1 (100, 200, and 400 microM) and NARG (100 microM) were perfused over 20 min. In both striatum and CA1 SIN-1 increased extracellular concentrations of GLU (maximal increase 150% and 197% of baseline, respectively) and GABA (maximal increase 202% and 204% of baseline, respectively). NARG had no effects on extracellular levels of GLU and GABA in either area. These results are consistent with the hypothesis that NO acts as a modulator of GLU and GABA release in both striatum and hippocampus. This study is the first to report the potentiation of GLU and GABA release by NO in CA1 area of the hippocampus in the conscious rat.
Electrophysiological studies suggest that 5-HT autoreceptor desensitization may be responsible for the delayed clinical efficacy of some antidepressant drugs, such as selective 5-HT reuptake inhibitors (SSRI) and certain MAO inhibitors (MAOI). In the present study we have used in vivo microdialysis to test this hypothesis. Rats were treated for 2 weeks with the antidepressant SSRI citalopram (5 mg/kg, s.c., b.i.d.). After 24 hr withdrawal, dialysis probes were implanted in the dorsal hippocampus (DH) and the frontal cortex (FCx). The rats then received as acute challenge, a 5-HT1A autoreceptor-active dose of the reference 5-HT1A agonist 8-OH-DPAT (0.025 mg/kg s.c.). The 8-OH-DPAT-induced changes in dialysate 5-HT from the DH and the FCx were monitored and taken as an index of autoreceptor sensitivity. Chronic citalopram and control animals responded similarly to 8-OH-DPAT with a drop of 5-HT of about 50-65%; no significant difference between the chronic citalopram and control groups were obtained, either in the DH or in the FCx. These data suggest that cell body 5-HT1A autoreceptors do not desensitize in response to repeated administration with antidepressant SSRI drugs such as citalopram.
Chronic (14 daily injections) treatment of mice with the prototypic tricyclic antidepressant imipramine significantly alters ligand binding to the N-methyl-D-aspartate (NMDA) receptor complex. These effects were compared to a chronic regimen of 1-aminocyclopropanecarboxylic acid, a high-affinity partial agonist at strychnine-insensitive glycine receptors which mimics the effects of imipramine in preclinical models predictive of antidepressant action. Changes in the NMDA receptor complex after chronic, but not acute treatment with imipramine were manifested as: 1) a reduction in the potency of glycine to inhibit [3H]5,7-dichlorokynurenic acid binding to strychnine-insensitive glycine receptors; 2) a decrease in the proportion of high-affinity glycine sites inhibiting [3H]CGP 39653 binding to NMDA receptors; and 3) a decrease in basal [3H]MK-801 binding (under nonequilibrium conditions) to sites within NMDA receptor-coupled cation channels which was reversible by the addition of glutamate. These effects were observed in cerebral cortex, but not in hippocampus, striatum or basal forebrain. Chronic treatment with 1-aminocyclopropanecarboxylic acid resulted in changes which paralleled those of imipramine on ligand binding to the NMDA receptor complex, but the reduction in basal [3H]MK-801 binding did not achieve statistical significance. These findings indicate that adaptive changes in the NMDA receptor complex could be a feature common to chronic treatment with structurally unrelated antidepressants.
Nitric oxide (NO) is becoming recognized as an important intercellular messenger in the brain. The present experiment used microdialysis to examine the potential role of NO in the regulation of dopamine (DA) and serotonin (5-HT) release in the medial preoptic area (MPOA) of freely moving male rats. The NO precursor L-arginine (L-Arg, 100 microM), administered into the MPOA via the dialysis probe, increased extracellular levels of DA, 5-HT, and the major metabolites of DA. These increases were blocked by the coadministration of the NO synthase inhibitor N-monomethyl L-arginine (NMMA, 400 microM). The inactive isomer D-arginine (100 microM) was ineffective, and NMMA by itself decreased DA below baseline levels. Thus, NO may modulate the release of DA and 5-HT in the MPOA.
This study was carried out to investigate plasma levels of excitatory amino acids, such as glutamate and aspartate, and glutamine, serine, glycine, taurine and histidine in major depression. The plasma amino acids were determined by means of HPLC in 22 normal controls and 25 unmedicated patients with major depression. Major depression was characterized by higher plasma taurine levels than normal controls. Significantly lower plasma glycine values and a higher serine/glycine ratio were observed in the depressed group. No significant differences in glutamine, histidine, serine or aspartate levels could be detected between the study groups. By means of linear discriminant analysis, a highly significant separation between major depressed subjects and normal volunteers was found using glycine, glutamate and taurine as discriminatory variables. No significant relationships between any of the amino acids and severity of depression could be found. The results suggest that major depression is accompanied by perturbations in the serine/glycine ratio, excitatory amino acids, such as glutamate, and inhibitory amino acids, such as taurine.
NMDA receptor antagonists have been shown to be anxiolytic in animal models of anxiety, although they have not been tested extensively. These compounds bind to several specific sites within the NMDA-receptor complex, including the NMDA site itself, the phencyclidine site, and the strychnine-insensitive glycine site. The purpose of the present study was to examine potential anxiolytic effects of site-selective NMDA receptor antagonists in the elevated plus-maze. Drug-naive albino mice were placed in the center of an elevated maze shaped like a plus sign. Two opposing arms were enclosed by high walls; the crossing arms were open. Following injection with drug or vehicle, the number of entries and time spent in each type of arm were measured during 5-min tests. Analysis of results showed that the benzodiazepine, diazepam, and the competitive NMDA receptor antagonist, NPC 17742 (2R,4R,5S 2-amino-4,5-(1,2-cyclohexyl)-7-phosphono-heptanoic acid), increased number of open arm entries and open arm time. N-Nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor which may interfere with the transduction of NMDA receptor activation, also increased open arm entries and time; however, the magnitude of these increases was small. The phencyclidine-site NMDA receptor antagonist, phencyclidine, increased open arm entries, but failed to significantly increase open arm time. ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione), a putative glycine-site antagonist, had significant effects only on open arm entries at the highest dose tested. These results suggest that NMDA receptor antagonists show promise as potential anxiolytic agents, but that differences among antagonists acting at different cellular sites may be expected.
In microdialysis studies, somatodendritic 5-HT1A receptors in the dorsal raphe nucleus (DRN) were activated by the local infusion of 50 microM citalopram, a selective 5-HT reuptake inhibitor (SSRI). This reduced extracellular 5-HT by about 50% in dorsal striatum, an area receiving 5-HT afferents exclusively from the DRN. (-)Pindolol dose-dependently attenuated this citalopram-induced reduction of striatal extracellular 5-HT. Consistent with its 5-HT reuptake blocking properties, single doses of the SSRI paroxetine (1 and 3 mg/kg IP) and citalopram (1 mg/kg IP) significantly elevated extracellular 5-HT in the dorsal striatum. Pretreatment with (-)pindolol (15 mg/kg IP) potentiated the effect of 3 mg/kg paroxetine and 1 mg/kg citalopram on striatal extracellular 5-HT. A 2-day treatment with 10 mg/kg/day (SC) of paroxetine reduced by 60% the spontaneous activity of 5-HT neurons of the DRN. However, 5-HT neurons displayed normal activity in rats treated with paroxetine and (-)pindolol for 2 days. The inhibitory effect of LSD on 5-HT neuronal firing activity was also markedly attenuated in (-)pindolol-treated rats, indicating that somatodendritic 5-HT1A receptors were blocked by (-)pindolol. To determine whether (-)pindolol also blocked postsynaptic 5-HT1A receptors in hippocampus, 5-HT and the prototypical 5-HT1A agonist 8-OH-DPAT were applied by microiontophoresis onto CA3 pyramidal neurons following the same treatment. (-)Pindolol did not modify the responsiveness of these neurons to 5-HT and 8-OH-DPAT. Taken together, these results indicate that (-)pindolol can potentiate the effects of an SSRI on extracellular 5-HT concentration by preventing the activation of somatodendritic 5-HT1A autoreceptors resulting from the blockade of the 5-HT transporter in the raphe. This presumably leads to enhanced 5-HT neurotransmission because (-)pindolol would not alter the responsiveness of certain postsynaptic 5-HT1A receptors, such as those located on hippocampal CA3 pyramidal neurons. These results provide a neurobiological basis for the reported potentiation of certain antidepressant drugs by pindolol in major depression.
The selective serotonin reuptake inhibitor, paroxetine, has been reported to inhibit cytochrome P450 activity. Nitric oxide synthase (NOS) is structurally homologous to cytochrome P450. Accordingly, in our study, we observed the effects of paroxetine on NOS activity. Seventeen ischemic heart disease (IHD) patients received paroxetine and fourteen received nortriptyline for treatment of clinical depression defined by a score of 17 or higher on the Hamilton Rating Scale for Depression (HAM-D). Serum nitrite and nitrate levels were significantly decreased following paroxetine treatment but not nortriptyline treatment. Paroxetine was also a more potent inhibitor of NOS enzyme activity than nortriptyline, as measured by the conversion of [14C] arginine to [14C] citrulline by hamster brain cytosols. In addition, paroxetine reversed the force-frequency relationship in isolated hamster papillary muscles in a manner analogous to that of known NOS inhibitors. Thus, paroxetine appears to be a novel NOS inhibitor in vitro and in vivo.
The involvement of nitric oxide (NO) in anxiety was investigated in rats, using the elevated plus maze test. Acute, but not chronic, systemic treatment with N omega-nitro-L-arginine methyl ester (L-NAME, 10 and 60 mg.kg-1), an inhibitor of NO synthase, increased the time spent by the rats in the open arms. Both the acute and chronic treatments with L-NAME inhibited NO synthase in endothelial cells and in the central nervous system, as shown by the increase in mean arterial pressure and decreased NO synthase activity in brain tissue. Chronic treatment with L-NAME also decreased the serum nitrate levels. The anxiolysis induced by acute L-NAME treatment is unlikely to be due to hypertension, since two-kidney one-clip hypertension in non-L-NAME-treated rats failed to significantly change exploratory behaviour in the elevated plus maze. These results indicate that acute inhibition of NO synthesis decreases anxiety in rats.
Previous reviews have well illustrated how antidepressant treatments can differentially alter several neurotransmitter systems in various brain areas. This review focuses on the effects of distinct classes of antidepressant treatments on the serotonergic and the noradrenergic systems of the hippocampus, which is one of the brain limbic areas thought to be relevant in depression: it illustrates the complexity of action of these treatments in a single brain area. First, the basic elements (receptors, second messengers, ion channels, ...) of the serotonergic and noradrenergic systems of the hippocampus are revisited and compared. Second, the extensive interactions occurring between the serotonergic and the noradrenergic systems of the brain are described. Finally, issues concerning the short- and long-term effects of antidepressant treatments on these systems are broadly discussed. Although there are some contradictions, the bulk of data suggests that antidepressant treatments work in the hippocampus by increasing and decreasing, respectively, serotonergic and noradrenergic neurotransmission. This hypothesis is discussed in the context of the purported function of the hippocampus in the formation of memory traces and emotion-related behaviors.
The action of the novel nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI) was studied in different exploratory models of anxiety. In the rat plus-maze test, 7-NI potently increased time spent on open arms and percentage of open arm visits in a dose dependent manner with the minimal effective dose of 40 mg/kg. 7-NI caused an anxiolytic-like effect in the rat social interaction test. The minimal dose increasing social interaction time was 20 mg/kg. However, the drug also produced a clear sedative effect occurring even at smaller doses (10 mg/kg) in the open field test. 7-NI also showed an anxiolytic-like profile in the mouse light-dark compartment test and in the elevated plus-maze test, but the doses required were higher (80-120 mg/kg) than in rat models. Also, the sedative effect occurred at these doses in open field. We failed to demonstrate any effect of L-arginine either in the rat elevated plus-maze test or in the open field test at doses up to 600 mg/kg IP. These results indicate that there are no major interspecies differences between rats and mice in respect of action of 7-NI. The clear anxiolytic-like action of the nitric oxide synthase inhibitor in four different models shows that nitric oxide is involved in the process of anxiety and that NOS could be a new target in developing anxiolytic drugs.
Potent inhibitors of nitric oxide synthase (NOS), 3-bromo-7-nitro indazole, 1-(2-trifluoromethylphenyl)imidazole, S-methyl-L-thiocitrulline and 7-nitro indazole, reduced locomotion in mice. These results suggest that activity of NOS and corresponding NO release are of importance for normal locomotion.
Several new antidepressants that inhibit the serotonin (SERT) and norepinephrine transporters (NET) have been introduced into clinical practice the past several years. This report focuses on the further pharmacologic characterization of nefazodone and its metabolites within the serotonergic and noradrenergic systems, in comparison with other antidepressants. By use of radioligand binding assays, we measured the affinity (Ki) of 13 antidepressants and 6 metabolites for the rat and human SERT and NET. The Ki values for eight of the antidepressants and three metabolites were also determined for the rat 5-HT1A, 5-HT2A and muscarinic cholinergic receptors, the guinea pig histamine1 receptor and the human alpha-1 and alpha-2 receptors. These data are useful for predicting side effect profiles and the potential for pharmacodynamic drug-drug interactions of antidepressants. Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a "dual uptake inhibitor", possesses weak affinity for the NET. We observed significant correlations in SERT (r = 0.965) or NET (r = 0.983) affinity between rat and human transporters. Significant correlations were also observed between muscarinic cholinergic and NET affinity. There are several significant correlations between affinities for the 5-HT1A, 5-HT2A, histamine1, alpha-1 and alpha-2 receptors. These novel findings, not widely described previously, suggest that many of the individual drugs studied in these experiments possess some structural characteristic that determines affinity for several G protein-coupled, but not muscarinic, receptors.
The aim of the present study was to investigate the effect of methylene blue, a guanylate cyclase inhibitor, on the hippocampal nitric oxide synthase activity in vivo. We used a microdialysis-based technique of measuring conversion of [3H]l-arginine to [3H]l-citrulline in freely moving rats. The administration of methylene blue (0.1 and 1 mM) via the microdialysis probe caused a dose-dependent decrease in [3H]l-citrulline efflux comparable with the effect of unselective NOS inhibitor NG-nitro-L-arginine (2 mM). We conclude that methylene blue inhibits brain NOS activity in vivo and thus interferes with NO-cGMP cascade in different levels.
Previous studies have demonstrated that antagonists at the NMDA receptor are as efficacious as tricyclic antidepressants in pre-clinical antidepressant screening procedures and in blocking or reversing the behavioral deficits associated with animal analogs of major depressive symptomatology. The NMDA receptor complex gates Ca2+, which interacts with calmodulin to subsequently activate nitric oxide (NO) synthase. We hypothesized that NO synthase antagonists might display antidepressant-like properties, similar to NMDA receptor antagonists. We examined the effects of N(G)-nitro-L-arginine (L-NNA), its dextrorotatory enantiomer, D-NNA, N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) at doses from 1 to 30 mg/kg in the forced swim test in mice. We now report that NO synthase antagonists are as efficacious as imipramine (15 mg/kg) in reducing the duration of immobility in the mouse forced swim test. The effects of NO synthase antagonists, as well as those of imipramine were blocked by pre-treatment with L-arginine (L-Arg) (500 mg/kg). In contrast to imipramine, the NO synthase antagonists were without effect on locomotor activity over the dose range active in the forced swim test (3-10 mg/kg). Likewise, L-Arg was without effect on locomotor activity. These data support the hypothesis that NO synthase antagonists possess antidepressant properties and may represent a novel class of therapeutics for major depressive disorders.
To investigate the effect of nitric oxide (NO) on the release of serotonin and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), the posterior hypothalamus of the conscious rat was superfused through a push-pull cannula with drugs which either liberate NO, or inhibit NO synthase (NOS). The NO donors, linsidomine, diethylamine/nitric oxide (DEA/NO), S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-glutathione (SNOG) and sodium nitroprusside influenced the release of serotonin in a biphasic way. Low concentrations of drugs diminished, while higher concentrations of these compounds enhanced the outflow of serotonin. The NOS inhibitors N(G)-methyl-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NINA) enhanced the serotonin release. A high concentration of L-NAME slightly diminished the outflow of serotonin. Inhibition of the guanylyl cyclase by oxodiazolo[4, 3]quinoxaline-one (ODQ) abolished the changes in serotonin outflow induced by both low and high concentrations of linsidomine. The extracellular concentration of the 5-HIAA was not influenced by the compounds used. These data suggest that endogenous NO modulates the release of serotonin in a biphasic and cGMP-dependent way.
Despite a remarkable structural diversity, most conventional antidepressants may be viewed as 'monoamine based', increasing the synaptic availability of serotonin, norepinephrine, and/or dopamine. Both preclinical and recent clinical studies indicate that compounds which reduce transmission at N-methyl-D-aspartate (NMDA) receptors are antidepressant. Moreover, chronic administration of antidepressants to mice alters both the mRNA levels encoding N-methyl-D-aspartate receptor subunits and radioligand binding to these receptors within circumscribed areas of the central nervous system. It is hypothesized that these two different treatment strategies converge to produce an identical functional endpoint: a region-specific dampening of NMDA receptor function. The pathways leading to this convergence provide a rudimentary framework for discovering novel antidepressants.
Nitric oxide synthase (NOS) is an enzyme involved in the activation of the glutamate/NMDA receptor-induced cascade of events. In this study we investigated the NOS activity in different rat brain regions after chronic electroconvulsive, imipramine and citalopram treatments. Chronic electroconvulsive treatment significantly increased the NOS activity (by 49%) in the cerebral cortex. However, chronic treatment with imipramine or citalopram did not alter the activity of NOS in all examined brain regions (cortex, hippocampus or cerebellum). The increased NOS activity after electroconvulsive but not pharmacologic (imipramine or citalopram) treatment may well reflect the differences between the adaptive changes of the NMDA receptor complex induced by these treatments.
Striatal neurones receive myriad of synaptic inputs originating from different sources. Massive afferents from all areas of the cortex and the thalamus represent the most important source of excitatory amino acids, whereas the nigrostriatal pathway and intrinsic circuits provide the striatum with dopamine, acetylcholine, GABA, nitric oxide and adenosine. All these neurotransmitter systems interact each other and with voltage-dependent conductances to regulate the efficacy of the synaptic transmission within this nucleus. The integrative action exerted by striatal projection neurones on this converging information dictates the final output of the striatum to the other basal ganglia structures. Recent morphological, immunohistochemical and electrophysiological findings demonstrated that the striatum also contains different interneurones, whose role in physiological and pathological conditions represents an intriguing challenge in these years. The use of the in vitro brain slice preparation has allowed not only the detailed investigation of the direct pre- and postsynaptic electrophysiological actions of several neurotransmitters in striatal neurones, but also the understanding of their role in two different forms of corticostriatal synaptic plasticity, long-term depression and long-term potentiation. These long-lasting changes in the efficacy of excitatory transmission have been proposed to represent the cellular basis of some forms of motor learning and are altered in animal models of human basal ganglia disorders, such as Parkinson's disease. The striatum also expresses high sensitivity to hypoxic-aglycemic insults. During these pathological conditions, striatal synaptic transmission is altered depending on presynaptic inhibition of transmitter release and opposite membrane potential changes occur in projection neurones and in cholinergic interneurones. These ionic mechanisms might partially explain the selective neuronal vulnerability observed in the striatum during global ischemia and Huntington's disease.
The concept that neural activity is important for brain maturation has focused much research interest on the developmental role of the NMDA receptor, a key mediator of experience-dependent synaptic plasticity. However, a mechanism able to link spatial and temporal parameters of synaptic activity during development emerged as a necessary condition to explain how axons segregate into a common brain region and make specific synapses on neuronal sub-populations. To comply with this developmental constraint, it was proposed that nitric oxide (NO), or other substances having similar chemical and biological characteristics, could act as short-lived, activity-dependent spatial signals, able to stabilize active synapses by diffusing through a local volume of tissue. The present article addresses this issue, by reviewing the experimental evidence for a correlated role of the activity of the NMDA receptor and the production of NO in key steps of neural development. Evidence for such a functional coupling emerges not only concerning synaptogenesis and formation of neural maps, for which it was originally proposed, but also for some earlier phases of neurogenesis, such as neural cell proliferation and migration. Regarding synaptogenesis and neural map formation in some cases, there is so far no conclusive experimental evidence for a coupled functional role of NMDA receptor activation and NO production. Some technical problems related to the use of inhibitors of NO formation and of gene knockout animals are discussed. It is also suggested that other substances, known to act as spatial signals in adult synaptic plasticity, could have a role in developmental plasticity. Concerning the crucial developmental phase of neuronal survival or elimination through programmed cell death, the well-documented survival role related to NMDA receptor activation also starts to find evidence for a concomitant requirement of downstream NO production. On the basis of the reviewed literature, some of the major controversial issues are addressed and, in some cases, suggestions for possible future experiments are proposed.
There is some strong evidence about the role of nitric oxide (NO) as an intercellular messenger in central physiological mechanisms. NO is synthesized from L-arginine by nitric oxide synthase (NOS), as a response to activation of N-methyl-D-aspartate (NMDA) receptors by excitatory amino acids. NMDA receptor antagonists also produce antidepressant-like actions in preclinical models.
In the present study, the involvement of NO in the mechanism of depression was investigated. 7-Nitroindazole (7-NI) (15, 30, 60, 90 mg/kg IP), a selective inhibitor of neuronal NOS was examined.
The Porsolt forced swimming test (FST) has been used as a test for screening new antidepressant agents.
7-NI dose-dependently decreased the immobility time in FST, but produced no significant change in locomotor activity in naive rats. Neither L-arginine, nor D-arginine (100 mg/kg) affected the immobility time in the FST or revealed any effect on locomotion. L-Arginine but not D-arginine, given 10 min before 7-NI, reversed the 7-NI-induced effect on immobility time.
Our findings suggest that NO might be an important modulator of depression in rats.
Nitric oxide (NO) modulates the levels of various neurotransmitters in the CNS. Here we determined whether the specific nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI), the non-selective inhibitor of guanylate cyclase (GC) and NOS, methylene blue (MB), the NO-precursor L-arginine (L-Arg), and the selective soluble GC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) affect extracellular levels of serotonin (5-HT), dopamine (DA), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) in the rat ventral hippocampus by using microdialysis in freely moving animals.
Local perfusion of 7-NI (1 mM) and MB (1 mM) significantly increased extracellular level of 5-HT, whereas DA was increased by 7-NI only. Systemic administration of 7-NI (50 mg kg−1) and MB (30 mg kg−1) increased the extracellular levels of 5-HT and DA. Extracellular levels of 5-HIAA was not influenced by local or systemic MB or 7-NI. In contrast, extracellular level of HVA was decreased by systemic MB and retrodialyzed MB, but was not influenced by 7-NI.
Retrodialysis of L-Arg (2 mM) decreased the levels of 5-HT, DA, 5-HIAA and HVA in the hippocampus. Systemic administration of L-Arg (250 mg kg−1) decreased the level of 5-HT, but failed to influence DA, 5-HIAA and HVA.
Local perfusion of ODQ (400 μM) did not affect 5-HT overflow in the hippocampus.
We conclude that NOS inhibitors increased extracellular levels of 5-HT and DA in the rat ventral hippocampus after local or systemic administration, whereas the NO precursor L-Arg had the opposite effect. Thus, endogenous NO may exert a negative control over the levels of 5-HT and DA in the hippocampus. However, this effect is probably not mediated by cyclic GMP.
British Journal of Pharmacology (2000) 130, 575–580; doi:10.1038/sj.bjp.0703349
A substantial number of patients do not respond sufficiently to antidepressant drugs and are therefore often co-medicated with lithium as an augmentative strategy. Since lithium has been demonstrated to affect 5-HT neurotransmission, we examined the effect of acute and subchronic lithium on 5-HT levels after a challenge with citalopram. We found that subchronic administration of lithium increases extracellular 5-HT baseline level and decreases the extracellular 5-HIAA baseline. However, we found no evidence that the effect of acute citalopram on extracellular 5-HT levels is augmented by acute or subchronic lithium.
The roles of the N-methyl-D-aspartate (NMDA) receptor and NMDA receptor-mediated synaptic plasticity are reviewed in the context of depressive disorder and its treatment. The mode of action of antidepressant treatment is poorly understood. Animal studies have suggested that many antidepressant drugs show activity at the NMDA receptor and that NMDA antagonists have antidepressant profiles in preclinical models of depression. A post-mortem study in humans has suggested that certain binding characteristics of the NMDA receptor may be down-regulated in the brains of suicide victims. "Depressogenic" stressors in animals and chronic administration of antidepressant agents perturb NMDA-dependent synaptic plasticity in the hippocampus.