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Simplified diagram of basal ganglia nuclei and connections . Note the distribution of dopamine-receptor subtypes (D1, D2) and neuropeptides between the two striatal output pathways. Neurons that project to the substantia nigra and/or the entopeduncular nucleus ± the ªdirectº pathway ± contain dynorphin (DYN) and substance P (SP) in addition to the inhibitory neurotransmitter GABA. Neurons that project to the globus pallidus ± the first segment of the ªindirectº pathway ± contain enkephalin (ENK) and GABA. DA Dopamine, SN substantia nigra, PC pars compacta, PR pars reticulata, VTA ventral tegmental area
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Projection neurons in the striatum give rise to two output systems, the "direct" and "indirect" pathways, which antagonistically regulate basal ganglia output. While all striatal projection neurons utilize GABA as their principal neurotransmitter, they express different opioid peptide co-transmitters and also different dopamine receptor subtypes. N...
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In the past few years, a number of laboratories have used gene targeting via homologous recombination to generate mice deficient for key molecules involved in dopaminergic (DAergic) transmission. This tremendous effort has resulted in the successful generation and characterization of mice deficient for the neurotransmitter DA, the main terminator o...
Citations
... Tis fnding is intriguing because patients in the mutant group were more sensitive to pain. A study has stated that the neuronal content of enkephalins is decreased by the chronic activation of dopaminergic neurotransmission in vivo [33]. Te reduction in enkephalin content upregulates the µ-opioid receptors in various regions of the brain [11,33]. ...
... A study has stated that the neuronal content of enkephalins is decreased by the chronic activation of dopaminergic neurotransmission in vivo [33]. Te reduction in enkephalin content upregulates the µ-opioid receptors in various regions of the brain [11,33]. Decreased COMT enzyme activity caused by the COMT Val158Met gene mutation may enhance dopaminergic activity and, therefore, reduce the enkephalin content, followed by the upregulation of µ-opioid receptor density. ...
Purpose. Catechol-O-methyltransferase (COMT) participates in the regulation of dopaminergic and adrenergic neurotransmission. COMT Val158Met polymorphism influences the efficacy and safety of opioids, but its association with oxycodone treatment in patients with cancer pain is yet to be elucidated. Hence, this study aimed to investigate the influence of COMT Val158Met polymorphism on oxycodone requirements, drug adverse effects, and pain sensitivity in patients with cancer. Methods. Patients with moderate to severe cancer pain treated with oxycodone were enrolled, of which 101 patients completed the study. All patients were genotyped for COMT Val158Met polymorphism using DNA from blood samples and were categorized into the wild-type group (n = 50) comprising individuals with the Val/Val genotype and the mutant group (n = 51) encompassing those with the Val/Met or Met/Met genotype. Numerical rating scale (NRS) scores, oxycodone requirements, and the incidence of oxycodone-related adverse drug reactions were compared between the two groups. Results. Patients in the mutant group exhibited higher NRS scores (6.18 ± 1.40) before the oxycodone treatment than those in the wild-type (5.48 ± 1.54) group (P=0.017). Patients in the wild-type group required more oxycodone (96.00 ± 146.19 mg/24 h) than those in the mutant (77.25 ± 83.91 mg/24 h) group (P=0.0365). The incidence rates of dysuria (2.0% vs. 16.0%, P=0.016) and fatigue (0.0% vs. 12.0%, P=0.013) were significantly lower in the mutant group than those in the wild-type group. Moreover, patients with at least one Met allele showed a lower risk of suffering from oxycodone-related side effects than those with the wild homozygote (41.2% vs. 68.0%, P=0.007). Conclusion. Genetic variations in the COMT Val158Met gene may contribute to variability in the efficacy and safety of oxycodone in cancer pain treatment. The findings from this study emphasize the potential of pharmacogenetics in personalizing pain management. Furthermore, oxycodone therapeutic strategies can be designed based on genetic polymorphisms.
... As a major neuropeptide relevant to mediating aversive behaviour, dynorphin is expressed in D1 receptor expressing striatal neurons (Steiner and Gerfen, 1998), as well as in D1-D2 neurons (Perreault et al., 2010) and may be under regulatory control of D1-D2 signaling in the latter. Therefore, we measured parameters of dynorphin signaling after chronic THC exposure. ...
Earlier age of cannabis usage poses higher risk of Cannabis Use Disorder and adverse consequences, such as addiction, anxiety, dysphoria, psychosis, largely attributed to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC) and altered dopaminergic function. As dopamine D1-D2 receptor heteromer activation causes anxiety and anhedonia, this signaling complex was postulated to contribute to THC-induced affective symptoms. To investigate this, we administered THC repeatedly to adolescent monkeys and adolescent or adult rats. Drug-naïve adolescent rat had lower striatal densities of D1-D2 heteromer compared to adult rat. Repeated administration of THC to adolescent rat or adolescent monkey did not alter D1-D2 heteromer expression in nucleus accumbens or dorsal striatum but upregulated it in adult rat. Behaviourally, THC-treated adult, but not adolescent rat manifested anxiety and anhedonia-like behaviour, with elevated composite negative emotionality scores that correlated with striatal D1-D2 density. THC modified downstream markers of D1-D2 activation in adult, but not adolescent striatum. THC administered with cannabidiol did not alter D1-D2 expression. In adult rat, co-administration of CB1 receptor (CB1R) inverse agonist with THC attenuated D1-D2 upregulation, implicating cannabinoids in the regulation of striatal D1-D2 heteromer expression. THC exposure revealed an adaptable age-specific, anxiogenic, anti-reward mechanism operant in adult striatum but deficient in adolescent rat and monkey striatum that may confer increased sensitivity to THC reward in adolescence while limiting its negative effects, thus promoting continued use and increasing vulnerability to long-term adverse cannabis effects.
... A number of studies have shown that FLX potentiates effects of MP on gene regulation in the striatum ( [5,[12][13][14]. For example, in a previous study [5], we used a chronic oral treatment regimen (in drinking water) that produces clinically relevant drug plasma levels [15] and found that MP+FLX induced changes in gene expression for the neuropeptides dynorphin and substance P, both markers for the direct output pathway of the striatum [16], which is predominantly affected by various psychostimulant treatments [11]. In this study, exposure to MP alone induced marginal increases in dynorphin and substance P mRNA levels [5]. ...
Background
Depression and attention deficit hyperactivity disorder are known to be comorbid. Treatment of these commonly coexisting diseases typically involves the combined prescription of methylphenidate (MP), a psychostimulant, and fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI). MP and cocaine have similar mechanisms of action and this study examined the effects of chronic treatment of MP combined with FLX on cocaine consumption in rats.
Methods
Four groups of rats received access to drinking solutions of water (control), MP (30/60 mg/kg/day), FLX (20 mg/kg/day), or the combination of MP (30/60 mg/kg/day) plus FLX (20 mg/kg/day), during 8 h per day for one month. Following these drug treatments, rats were allowed to self-administer cocaine for 14 days.
Results
Our results showed that, during the first week of cocaine self-administration, the MP-treated rats had significantly greater numbers of active lever presses (plus 127%) and increased consumption of cocaine compared to the control rats. In contrast, during week two of cocaine self-administration, the rats treated with the MP + FLX combination showed significantly more lever presses (plus 198%) and significantly greater cocaine consumption (plus 84%) compared to the water controls.
Conclusion
Chronic oral treatment during adolescence with the combination of MP plus FLX resulted in increased cocaine use after 2 weeks of cocaine self-administration in rats. These novel findings suggest that the combined exposure to these two drugs chronically, during adolescence, may produce increased vulnerability towards cocaine abuse during young adulthood.
... The major projection neurons in the NAc are medium spiny neurons (MSNs), distinguished by their dopamine receptor expression (D1-MSNs and D2-MSNs) [23][24][25]. Markers for D1-MSNs and D2-MSNs also include the expression of different peptides [26,27]. Substance P, the major peptide encoded by tachykinin precursor 1 gene (TAC1), and dynorphin are exclusively expressed in D1-MSNs [28][29][30]. ...
Neural circuits that control aversion are essential for motivational regulation and survival in animals. The nucleus accumbens (NAc) plays an important role in predicting aversive events and translating motivations into actions. However, the NAc circuits that mediate aversive behaviors remain elusive. Here, we report that tachykinin precursor 1 (Tac1) neurons in the NAc medial shell regulate avoidance responses to aversive stimuli. We show that NAcTac1 neurons project to the lateral hypothalamic area (LH) and that the NAcTac1→LH pathway contributes to avoidance responses. Moreover, the medial prefrontal cortex (mPFC) sends excitatory inputs to the NAc, and this circuit is involved in the regulation of avoidance responses to aversive stimuli. Overall, our study reveals a discrete NAc Tac1 circuit that senses aversive stimuli and drives avoidance behaviors.
... Long-term cocaine treatment (≥15 mg/kg × ≥ 10 days) is reported to increase Penk mRNA expression in the striatum (Crespo et al., 2001;Mantsch et al., 2004;Mathieu-Kia and Besson, 1998;Mongi-Bragato et al., 2016). Evidence suggests this effect is through longterm cocaine treatment downregulating D2R activity (Baik et al., 1995;Moore et al., 1998;Nader et al., 2002Nader et al., , 2006Romano et al., 1987;Steiner and Gerfen, 1998) Moore et al., 1998a,b. Given our data showing the connection between striatal Drd2 and Penk expression, we hypothesized the length of cocaine treatment would similarly bidirectionally regulate striatal Penk expression by targeting D2Rs in MSNs. ...
... This cell-intrinsic adaptation in response to altered dopamine transmission has been previously suggested in reports with dopamine-depleted mice. Enhanced Penk expression following 6-OHDA lesions is proposed as an adaptive mechanism to maintain balance in striatal output, as it correlates with partial recovery of motor impairment (Steiner and Gerfen, 1998). However, this Penk enhancement may also generate vulnerability to cocaine seeking by suppressing collateral GABA transmission onto D1-MSNs and ultimately promoting their output. ...
Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist. In brain slices, met-enkephalin and inhibition of enkephalin catabolism suppresses intra-striatal GABA transmission. Pairing cocaine with intra-accumbens met-enkephalin during place conditioning facilitates acquisition of preference, while mu-opioid receptor antagonist blocks preference in wild-type mice. We propose that heightened striatal enkephalin potentiates cocaine reward by suppressing intra-striatal GABA to enhance striatal output. Surprisingly, a mu-opioid receptor antagonist does not block cocaine preference in mice with low striatal D2Rs, implicating other opioid receptors. The bidirectional regulation of enkephalin by D2R activity and cocaine offers insights into mechanisms underlying the vulnerability for cocaine abuse.
... We assessed the impact of these treatments on the expression of dynorphin and enkephalin as markers for D1-MSNs and D2-MSNs, respectively [21]. The effects of the dopamine depletion and subsequent repeated L-DOPA treatment (groups 6/V and 6/LD) on these neuropeptides have been reported in detail before [14] and are summarized here. ...
... We assessed the impact of acute psychostimulant treatment on the expression of the immediate-early gene zif268 and the neuropeptide substance P, a marker for acute changes in D1-MSNs [21], in adolescents. Overall, the zif268 expression was significantly increased by cocaine (25 mg/kg) in 20 of the 23 sectors and by methylphenidate (5 mg/kg) in 15 sectors. ...
... In marked contrast to these positive correlations between local PDE10A expression and the enkephalin or 5-HT1B expression, the decreases in dynorphin expression (D1-MSNs) after dopamine depletion, considered to reflect decreased activity in D1-MSNs after the loss of stimulatory D1 receptor activity [21], were unrelated to local PDE10A expression, suggesting no contribution of PDE10A to these effects. ...
Dopamine and other neurotransmitters have the potential to induce neuroplasticity in the striatum via gene regulation. Dopamine receptor-mediated gene regulation relies on second messenger cascades that involve cyclic nucleotides to relay signaling from the synapse to the nucleus. Phosphodiesterases (PDEs) catalyze cyclic nucleotides and thus potently control cyclic nucleotide signaling. We investigated the role of the most abundant striatal PDE, PDE10A, in striatal gene regulation by assessing the effects of PDE10A inhibition (by a selective PDE10A inhibitor, TP-10) on gene regulation and by comparing the basal expression of PDE10A mRNA throughout the striatum with gene induction by dopamine agonists in the intact or dopamine-depleted striatum. Our findings show that PDE10A expression is most abundant in the sensorimotor striatum, intermediate in the associative striatum and lower in the limbic striatum. The inhibition of PDE10A produced pronounced increases in gene expression that were directly related to levels of local PDE10A expression. Moreover, the gene expression induced by L-DOPA after dopamine depletion (by 6-OHDA), or by psychostimulants (cocaine, methylphenidate) in the intact striatum, was also positively correlated with the levels of local PDE10A expression. This relationship was found for gene markers of both D1 receptor- and D2 receptor-expressing striatal projection neurons. Collectively, these results indicate that PDE10A, a vital part of the dopamine receptor-associated second messenger machinery, is tightly linked to drug-induced gene regulation in the striatum. PDE10A may thus serve as a potential target for modifying drug-induced gene regulation and related neuroplasticity.
... Dynorphin, enkephalin, and tachykinin neuropeptides of the basal ganglia have many effects, including regulation of neurotransmitter release, modulation of blood-brain barrier permeability, and stimulation of neuro-inflammatory responses [5][6][7][8][9] . The basal ganglia neuropeptides originate from the GABA (γ-aminobutyric acid)-ergic striatal spiny projection neurons (SPNs). ...
... The PDYN-derived signaling peptides αneoendorphin (α-neo), dynorphin (Dyn) A (1-8), and Dyn B were most abundant in the SN and their levels were elevated in the GPi of the LID animals ( Fig. 1c). TKN1-derived substance P (SP) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) was most abundant in the SN and GPi, while the PENK-derived met-enkephalin was highly abundant in the GPe (Fig. 1c). ...
... To further elucidate relationships between the neuropeptides and severity of dyskinesia, we examined the correlations between their abundances in specific brain regions and dyskinesia scores. Significant correlations were observed for two N-terminal truncated α-neo derivatives: α-neo (2-10) in the GPe, GPi, BCd and SN, and α-neo (3)(4)(5)(6)(7)(8)(9)(10) in the GPi and BCd. Conversely, dyskinesia scores did not correlate significantly with levels of the full α-neo signaling peptide ( Fig. 2c and Supplementary Table 3). ...
L-DOPA administration is the primary treatment for Parkinson’s disease (PD) but long-term administration is usually accompanied by hyperkinetic side-effects called L-DOPA-induced dyskinesia (LID). Signaling neuropeptides of the basal ganglia are affected in LID and changes in the expression of neuropeptide precursors have been described, but the final products formed from these precursors have not been well defined and regionally mapped. We therefore used mass spectrometry imaging to visualize and quantify neuropeptides in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposed parkinsonian and LID Macaca mulatta brain samples. We found that dyskinesia severity correlated with the levels of some abnormally processed peptides — notably, des-tyrosine dynorphins, substance P (1-7), and substance P (1-9) — in multiple brain regions. Levels of the active neuropeptides; dynorphin B, dynorphin A (1-8), α-neoendorphin, substance P (1-11), and neurokinin A, in the globus pallidus and substantia nigra correlated with putaminal levels of L-DOPA. Our results demonstrate that the abundance of selected active neuropeptides is associated with L-DOPA concentrations in the putamen, emphasizing their sensitivity to L-DOPA. Additionally, levels of truncated neuropeptides (which generally exhibit reduced or altered receptor affinity) correlate with dyskinesia severity, particularly for peptides associated with the direct pathway (i.e., dynorphins and tachykinins). The increases in tone of the tachykinin, enkephalin, and dynorphin neuropeptides in LID result in abnormal processing of neuropeptides with different biological activity and may constitute a functional compensatory mechanism for balancing the increased L-DOPA levels across the whole basal ganglia.
... They are highly expressed in human nervous system. By immunostaining techniques, the most intense enkephalin staining was found in the globuspallidus, substantianigra, caudate, and putamen [28,29], suggesting their role in the striatal control of motor and behavioral function [30,31]. Moreover, recent studies found an up-regulation of endogenous opioid enkephalin in the midbrain as a compensatory mechanism to alleviate PD-related motor symptoms [32][33][34]. ...
... Cytotoxicity was assessed quantitatively by measuring the lactate dehydrogenase (LDH) activity in the medium using the cytoscan-LDH cytotoxicity assay kit (G-Biosciences Inc., St Louis, Mo, USA) [15,29,30]. ...
Hypoxic/ischemic brain injury is a potential etiology of Parkinson’s disease (PD). There is evidence suggesting that the up-regulation of enkephalin, an endogenous opioid, in the midbrain may have a compensatory effect against Parkinson’s disease (PD) related motor symptoms. To explore the potential mechanism underlying this action, we investigated the effects of hypoxia and MPP ⁺ , a pathological inducer PD, on enkephalin, δ-opioid receptor (DOR, an enkephalin receptor), and prohormone convertases 1 and 2 (PC1/PC2) on in- vitro PD model of PC12 cells. We found that (1) short-term hypoxia could inducing cell protection by up-regulating the level of enkephalin, accompanied by the synergistic up-regulation of δ-opioid receptor (DOR) ; (2) a longer period of hypoxia or MPP ⁺ insult accelerated the proteolysis of proenkephalin by up-regulating PC1/PC2 which might produce more active enkephalin and thus activating DOR for cell protection; (3) The levels of enkephalin and DOR decreased significantly after a prolonged hypoxia or MPP ⁺ insult; and (4) a certain degree of hypoxia improved cell viability and enhance the transcription of dopamine D1/D2 receptorby increasing their mRNA level. Our findings suggest that hypoxia may induce an interactive reaction of enkephalin, DOR and dopamine receptor D1/D2, which is potentially beneficial for cell surviving to severe/prolonged hypoxia and PD condition.
... Related to the acetylcholinesterase-poor quality of striosomes is their enkephalin-rich quality, and the role of opioids in the striatum in general. While glutamate and GABA are the principal molecules of the motor pathways, with dopamine involved in the learning component of motor activity, endogenous opioids are paired co-transmitters in the respective direct and indirect pathway (Steiner and Gerfen, 1998;Hearing, 2019;Koob, 2020). Specifically, D1 receptor expressing cells of the direct pathway express dynorphin while D2 expressing cells of the indirect pathway express enkephalin (Steiner and Gerfen, 1998). ...
... While glutamate and GABA are the principal molecules of the motor pathways, with dopamine involved in the learning component of motor activity, endogenous opioids are paired co-transmitters in the respective direct and indirect pathway (Steiner and Gerfen, 1998;Hearing, 2019;Koob, 2020). Specifically, D1 receptor expressing cells of the direct pathway express dynorphin while D2 expressing cells of the indirect pathway express enkephalin (Steiner and Gerfen, 1998). Interestingly, neurons that express both substance P and enkephalin have been found in the striatum, with a higher proportion in the striosome regions (Besson et al., 1990;Wang et al., 2007). ...
... Recent evidence examining opioid expressing neurons in the SNS circuit found that roughly 50% of GABA neurons in the SNr have µ-opioid receptors (MORs) which, when activated, lead to the disinhibition of SNpc DA neurons and the processing of reward with drugs like heroin (Galaj and Xi, 2021). However, because the opioid and dopamine receptors are subject to expression change based on the experience of the being, further investigation is needed to examine this possibility (Steiner and Gerfen, 1998;Crittenden and Graybiel, 2011;Hearing, 2019). ...
A biological reward system is integral to all animal life and humans are no exception. For millennia individuals have investigated this system and its influences on human behavior. In the modern day, with the US facing an ongoing epidemic of substance use without an effective treatment, these investigations are of paramount importance. It is well known that basal ganglia contribute to rewards and are involved in learning, approach behavior, economic choices, and positive emotions. This review aims to elucidate the physiological role of striatonigrostriatal (SNS) spirals, as part of basal ganglia circuits, in this reward system and their pathophysiological role in perpetuating addiction. Additionally, the main functions of neurotransmitters such as dopamine and glutamate and their receptors in SNS circuits will be summarized. With this information, the claim that SNS spirals are crucial intermediaries in the shift from goal-directed behavior to habitual behavior will be supported, making this circuit a viable target for potential therapeutic intervention in those with substance use disorders.
... Consequently, a disruption in this system will likely cause many physiological responses and malfunctions [61]. Disruption in opioid functions is non-evitable in PD as opioid modulators are involved in the basal ganglia circuitry the center of PD pathophysiology: dynorphin is involved in the direct pathway while enkephalin is specialized in the indirect pathway making changes in their expression a likely outcome in PD [62]. As such, early studies regarding opioids in PD revealed an increase of enkephalin expression in the striatum with an increase in the GP in MPTP mice and marmosets reinforcing opioids evolvement in PD pathophysiology [63]. ...
Neuropeptides are bioactive molecules, made up of small chains of amino acids, with many neuromodulatory properties. Several lines of evidence suggest that neuropeptides, mainly expressed in the central nervous system (CNS), play an important role in the onset of Parkinson’s Disease (PD) pathology. The wide spread disruption of neuropeptides has been excessively demonstrated to be related to the pathophysiological symptoms in PD where impairment in motor function per example was correlated with neuropeptides dysregulation in the substantia niagra (SN). Moreover, the levels of different neuropeptides have been found modified in the cerebrospinal fluid and blood of PD patients, indicating their potential role in the manifestation of PD symptoms and dysfunctions. In this review, we outlined the neuroprotective effects of neuropeptides on dopaminergic neuronal loss, oxidative stress and neuroinflammation in several models and tissues of PD. Our main focus was to elaborate the role of orexin, pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), opioids, angiotensin, carnosine and many others in the protection and/or involvement in the neurodegeneration of striatal dopaminergic cells. Further studies are required to better assess the mode of action and cellular mechanisms of neuropeptides in order to shift the focus from the in vitro and in vivo testing to applicable clinical testing. This review, allows a support for future use of neuropeptides as therapeutic solution for PA pathophysiology.
