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Anxiolytic Effects in the Plus-Maze of 5-HT1A-Receptor Ligands in Dorsal Raphe and Ventral Hippocampus
Abstract
The response of rats naive to, or experienced with, the elevated plus-maze test of anxiety was observed following direct administration of the 5-HT1A-receptor agonist (+/-)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) (50, 100, or 200 ng) or antagonist tertatolol (3 micrograms) into the dorsal raphé nucleus or bilaterally into the ventral hippocampus. In rats naive to the plus-maze, neither drug had a significant effect when microinjected into the dorsal raphé nucleus. However, in rats experienced with the plus-maze, 8-OH-DPAT (100 and 200 ng) had significant anxiolytic effects when administered to the dorsal raphé nucleus, which were antagonised by tertatolol (3 micrograms); this suggests they were mediated by 5-HT1A receptors. Hyperactivity (increased number of closed-arm entries) was found following bilateral injection of 8-OH-DPAT (100 ng) into the ventral hippocampus of rats naive to the plus-maze. This was not completely antagonised by tertatolol (3 micrograms). Interestingly, tertatolol (3 micrograms) itself had an anxiolytic effect which was not antagonised by 8-OH-DPAT (100 ng), suggesting the effect was not mediated by 5-HT1A receptors, and indeed other actions of tertatolol, such as those on 5-HT1B or beta-adrenergic receptors could have been involved. In rats experienced with the plus-maze, tertatolol (3 micrograms) again had a significant anxiolytic effect when administered bilaterally to the ventral hippocampus, and again, this was not antagonised by 8-OH-DPAT (100 ng). These results demonstrate that both the intracerebral location of the injection and test experience profoundly influence the effects of 5-HT1A ligands on behaviour of rats in the elevated plus-maze test of anxiety.
... Selective inactivation of MRN 5-HT neurons can also be achieved by stimulating autoinhibitory 5-HT 1A receptors located at the soma and dendrites of these cells, which results in inhibition of neuronal firing and reduction of 5-HT release in innervated territories (Bosker et al., 1996; Dudley et al., 1999; Hajós et al., 1995; Kreiss and Lucki, 1994). The results so far reported consistently show that intra-MRN administration of different doses of the 5-HT 1A receptor agonist 8-OH-DPAT decreases anxiety in the elevated plus-maze (De Almeida et al., 1998; File et al., 1996), lightdark transition (Carli and Samanin, 1988; Vicente et al., 2008), contextual conditioning (Almada et al., 2009; Avanzi and Brandão, 2001; Borelli et al., 2005; Silva et al., 2002, 2004), ultrasonic vocalization (Schreiber and De Vry, 1993), social interaction (Andrews et al., 1994; File et al., 1996) and punishment (Carli and Samanin, 1988) tests. ...
... Selective inactivation of MRN 5-HT neurons can also be achieved by stimulating autoinhibitory 5-HT 1A receptors located at the soma and dendrites of these cells, which results in inhibition of neuronal firing and reduction of 5-HT release in innervated territories (Bosker et al., 1996; Dudley et al., 1999; Hajós et al., 1995; Kreiss and Lucki, 1994). The results so far reported consistently show that intra-MRN administration of different doses of the 5-HT 1A receptor agonist 8-OH-DPAT decreases anxiety in the elevated plus-maze (De Almeida et al., 1998; File et al., 1996), lightdark transition (Carli and Samanin, 1988; Vicente et al., 2008), contextual conditioning (Almada et al., 2009; Avanzi and Brandão, 2001; Borelli et al., 2005; Silva et al., 2002, 2004), ultrasonic vocalization (Schreiber and De Vry, 1993), social interaction (Andrews et al., 1994; File et al., 1996) and punishment (Carli and Samanin, 1988) tests. ...
... Fear potentiated startle (–) Silva et al., 2002; Borelli et al., 2005 Ibotenic acid Contextual conditioning (–) Melik et al., 2000 BZDR agonist Midazolam Elevated plus-maze (0) Gonzalez et al., 1998 Social Interaction (–) Gonzalez et al., 1998 5-HT 1A R agonists 8-OH-DPAT Elevated plus-maze (–) (–) in females File et al., 1996 De Almeida et al., 1998 Light-dark transition Punishment test ...
Although the role of the median raphe nucleus (MRN) in the regulation of anxiety has received less attention than that of the dorsal raphe nucleus (DRN) there is substantial evidence supporting this function. Reported results with different animal models of anxiety in rats show that whereas inactivation of serotonergic neurons in the MRN causes anxiolysis, the stimulation of the same neurons is anxiogenic. In particular, studies using the elevated T-maze comparing serotonergic interventions in the MRN and in the DRN indicate that the former affect only the inhibitory avoidance task, which has been related to generalized anxiety. In contrast, similar operations in the DRN change both the inhibitory avoidance and the one-way escape task, the latter being representative of panic disorder. Simultaneous injections of 5-HT-acting drugs in the MRN and in the dorsal hippocampus (DH) suggest that the MRN-DH pathway mediates the regulatory function of the MRN in anxiety. Overall, the results discussed in this review point to a relevant role of the MRN in the regulation of anxiety, but not panic, through the 5-HT pathway that innervates the DH.
... One distal amygdalar projection target implicated in anxiety-related behaviors is the ventral hippocampus (vHPC). 14,15 The vHPC shares robust reciprocal connections with the basolateral nucleus of the amygdala. 16,17 Subsequent studies have concluded that the ventral, but not the dorsal, hippocampus is required for the expression of anxiety-related behaviors in the elevated plus-maze (EPM) and open-field test (OFT). ...
... As shown in Figure 3, the average running distance in 1 WVD and 4WVD groups was 878.73 ± 203.65 m and 948.61 ± 162.61 m. There is no significant difference between 1WVD and 4WVD groups (t (14) = 55.25, P = .347, ...
Background
Previous studies have demonstrated that pre-exercise suppresses anxiety-like behavior, but the effects of different exercise times on vascular dementia induced anxiety-like behavior have not been well investigated.
Objective
The present study aims to investigate the underlying neurochemical mechanism of different pre-vascular-dementia exercise times on 5-HT and anxiety-like behavior in rats with vascular dementia.
Methods
32 Sprague-Dawley (SD) rats were randomly divided into 4 groups: sham group (S group, n = 8), vascular dementia group (VD group, n = 8), 1-week physical exercise and vascular dementia group (1WVD group, n = 8), and 4 weeks physical exercise and vascular dementia group (4WVD group, n = 8). 1 week and 4 weeks of voluntary wheel running were used as pre-exercise training. The vascular dementia model was established by bilateral common carotid arteries occlusion (BCCAo) for 1 week. But bilateral common carotid arteries were not ligated in the sham group. The level of hippocampal 5-HT was detected with in vivo microdialysis coupled with high-performance liquid chromatography (MD-HPLC). Elevated plus maze (EPM), open field (OF), and light/dark box test were used to test anxiety-like behavior.
Results
Compared with the C group, the hippocampal 5-HT was significantly decreased in the VD group after 1 week of ligated operation. The hippocampal 5-HT levels in 1WVD and 4WVD groups were substantially higher than the level in the VD group. The hippocampal 5-HT level has no significant difference among C, 1WVD, and 4WVD. Behavioral data suggested that the rats in the VD group developed obvious anxiety-like behavior after 1 week of ligation surgery. Still, the rats in 1WVD and 4WVD groups did not show significant anxiety-like behavior.
Conclusion
Both 1 week and 4 weeks of voluntary running wheel exercise can inhibit the anxiety-like behavior in rats with vascular dementia by upregulating 5-HT levels in the hippocampus in the VD model.
... The present study is the first to report anxiolytic-like effects of acute treatment with NLX-112 in mice using two well established methods of anxiety assessment: the OFT and the EPM. There was a clear and distinct change in behaviour in a range of parameters measured in these experiments between mice treated with NLX-112 and those treated with vehicle, which corresponds to data from previous studies investigating 5-HT 1A agonists in murine models of anxiety (File and Gonzalez 1996;Vicente et al. 2008;Toth 2003). ...
... *p < 0.05, **p < 0.01, ****p < 0.0001, compared to vehicle control (Con), Fishers LSD post-hoc test following significant mixed effects model one-way ANOVA for repeated measures somatodendritic 5-HT 1A receptors, potently and efficaciously reduced anxiety-related behaviour in a rat social interaction model (Depoortere et al. 2019). Considering the wide body of evidence demonstrating that anxiety-like behaviours are mediated by 5-HT 1A neuronal presynaptic receptors in the raphe nuclei (File and Gonzalez 1996;Cervo et al. 2000;Vicente et al. 2008;Akimova et al. 2009) and that activation of 5-HT 1A presynaptic receptors with NLX-112 in the (dots) and as mean ± SEM (bars). *p < 0.05, **p < 0.01 compared to control (Con), Fishers LSD post-hoc test following significant mixed effects model one-way ANOVA for repeated measures rat induces complete inhibition of electrical activity in the raphe nuclei (Lladó-Pelfort et al. 2012), it is likely that NLX-112 is exerting its anxiolytic-like benefits via activation of presynaptic autoreceptors. ...
Anxiety is amongst the commonest neuropsychiatric disorders, and there is a large body of evidence to suggest that abnormalities in serotonergic function are involved in its pathogenesis. Several studies have implicated 5-HT1A receptor activation in mitigating anxiety disorders, so this study investigated the acute effects of a highly selective, potent and efficacious 5-HT1A receptor full agonist, NLX-112 (a.k.a. befiradol, F13640), in middle-aged C57bl/6 J male mice. Video tracking was used to measure several parameters including time spent in the open and closed arms of an elevated plus maze (EPM), distance travelled and thigmotaxis in an open field test (OFT). At 0.1 to 1.0 mg/kg s.c., NLX-112 markedly decreased thigmotaxis and increased exploratory behaviour in the OFT and EPM assays. Hence, at 0.3 mg/kg, NLX-112 augmented locomotor activity in the centre of an open field arena by 164% and increased the time spent in the open arms of the EPM by 119% of control. These results indicate that anxiety-like behaviours in mice are significantly diminished with low doses of NLX-112. NLX-112 may therefore possess anxiolytic properties which complement its known activity in models of movement disorders.
... The effects in the elevated plus-maze of 8-OH-DPAT administration to the dorsal raphé nucleus were found to depend on the experience of the animal; thus, there was no anxiolytic effect of doses up to 200 ng in rats naive to the maze, whereas 100 ng was anxiolytic in rats with one previous 5 min trial in the maze . In both the social interaction test and the plus-maze, the anxiolytic effects of 8-OH-DPAT administration to the dorsal raphé nucleus were shown to be attributable to actions on 5-HT 1A receptors, because they were antagonized by the 5-HT 1A receptor antagonist tertatolol File and Gonzalez, 1996). In the social interaction test, the anxiolytic effect of 8-OH-DPAT in the median raphé nucleus has not yet been firmly identified as being mediated by 5-HT 1A receptors, because it has not been reversed by a 5-HT 1A receptor antagonist. ...
... In the social interaction study we used (ϩ)WAY 100135, a specific 5-HT 1A receptor antagonist (Fletcher et al., 1993), but one that is unsuitable for central administration and therefore was administered subcutaneously. In the plus-maze studies, we used (Ϯ)tertatolol (Jolas et al., 1993;Prisco et al., 1993), which is soluble at neutral pH in artificial cerebrospinal fluid (aCSF), and which has been used in previous studies Hogg et al., 1994;File and Gonzalez, 1996). In the social interaction test, the doses of 8-OH-DPAT were determined on the basis of those that were effective in our previous studies; in the elevated plus-maze, the dose of tertatolol was that used in our previous studies. ...
The purpose of this study was to determine the roles of the presynaptic 5-hydroxytryptamine 1A (5-HT 1A ) receptors in the median raphénucleus (MRN) and of the postsynaptic 5-HT 1A receptors in its projection area of the dorsal hippocampus in the social interaction and elevated plus-maze tests of anxiety. Direct administration of the 5-HT 1A receptor agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 200 ng) into the MRN had significant anxiolytic effects in all three test situations examined (social interaction, plus-maze trials 1 and 2). These anxiolytic effects were antagonized by a silent dose (200 ng) of the 5-HT 1A receptor antagonist WAY 100635, confirming that they were mediated by 5-HT 1A receptors. In contrast, after bilateral administration to the dorsal hippocampus, 8-OH-DPAT (100 ng) had significant anxiogenic effects in the social interaction test and in plus-maze trial 2. These anxiogenic effects were antagonized by silent doses of 5-HT 1A receptor antagonists [(+)WAY 100135, 10 mg/kg s.c., and intrahippocampal (±)tertatolol, 3 μg, respectively], confirming mediation by 5-HT 1A receptors. In rats naive to the plus-maze, neither 8-OH-DPAT (50, 100, or 200 ng) nor the 5-HT 1A receptor antagonist (±)tertatolol (3 μg) had any significant effect when administered to the dorsal hippocampus. This demonstrates that previous experience of a rat in the plus-maze has a major effect on the sensitivity of dorsal hippocampal 5-HT 1A receptors, as we have demonstrated previously for the 5-HT 1A receptors in the dorsal raphé nucleus. Overall, our results provide evidence that stimulation of the presynaptic 5-HT 1A receptors in the MRN results in an anxiolytic action, whereas stimulation of the post-synaptic 5-HT 1A receptors in its projection area results in an anxiogenic effect. These results are consistent with an overall reduction in 5-HT neurotransmission in the dorsal hippocampus having an anxiolytic effect, and they explain the relatively weak anxiolytic profile detected when 5-HT 1A receptor agonists are given systemically.
... There are several animal behavior paradigms used to model anxiety, from those the Elevated plus-maze test (EPM) is a test based on exploratory behavior and a natural aversion of an animal towards open and high places (Fernandez Espejo, 1997;Griebel, 1995;Pellow et al., 1985). The pivotal role in the anxietyrelated process in the EPM has been demonstrated to be played, besides others, by the central nucleus of amygdala, hippocampus and raphe nuclei (File and Gonzalez, 1996;Killcross et al., 1997;Walker and Davis, 2002). As far as the neurotransmitters connected to anxiety-related behavior are concerned, interactions . ...
... A growing number of evidence suggest the mesolimbic DA system (i.e. prefrontal cortex, nucleus accumbens, and amygdala, which are mostly associated with the reinforcing and locomotor effects of drugs), to be also significant for various aspects of anxiety (File and Gonzalez, 1996;Killcross et al., 1997;Pezze and Feldon, 2004;Walker and Davis, 2002). Besides the DA system, the 5-HT system is the most likely candidate to be involved, and it has been proposed that a rise in 5-HT increases anxiety (Handley, 1995;Robinson et al., 2006). ...
Different forms of anxiety-related behavior have been reported after a single drug use of many abused substances, however, less is known about how males and females are affected differently from exposure to various drugs. Furthermore, chronic prenatal methamphetamine (MA) exposure was shown to predispose the animal to an increased sensitivity to drugs administrated in adulthood. Using the Elevated plus-maze test (EPM), the first aim of the present study was to examine how male and female rats are affected by acute drug treatment with subcutaneously (s.c.) administrated (a) MA (1 mg/kg); (b) drugs with a similar mechanism of action to MA: amphetamine (AMP, 1 mg/kg), cocaine (COC, 5 mg/kg), 3,4-methylenedioxymethamphetamine (MDMA, 5 mg/kg); and (c) drugs with different mechanisms of action: morphine (MOR, 5 mg/kg), and Δ 9-tetrahydrocannabinol (THC, 2 mg/kg). The second aim was to determine if prenatally MA-exposed (5 mg/kg) animals show an increased sensitivity to adult drug treatment. The parameters analyzed were divided into two categories: anxiety-related behavior and anxiety-unrelated/exploratory behavior. Our results showed in female rats a decreased percentage of the time spent in the closed arms (CA) after MA, and an increased percentage of the time spent in the open arms (OA) after MA, AMP, and COC treatment, indicating an anxiolytic-like effect. In females, MDMA and THC treatment increased the percentage of the time spent in the CA. An increased percentage of the time spent in the CA was also seen after MOR treatment in females as well as in males, indicating an anxiogenic-like effect. As far as the interaction between prenatal MA exposure and adult drug treatment is concerned, there was no effect found. In conclusion, it seems that: (a) in some cases female rats are more vulnerable to acute drug treatment, in terms of either anxiogenic- or anxiolytic-like effects; (b) prenatal MA exposure does not sensitize animals to the anxiety-related effects of any of the drugs.
... Elevated plus-maze test. The elevated plus-maze test has been widely used as a measure of anxiety, and the method used was as described elsewhere (File et al., 1993;File and Gonzalez, 1996). The plus-maze consists of two opposite open arms (45 ϫ 15 cm) and two opposite enclosed arms. ...
... On the first day of testing in the elevated plus-maze test, a naive rat will explore the open arms of the maze. The ratio of day 2/day 1 in open arm entries and visiting time usually decreases as the rats become aware of the danger of falling (File et al., 1993;File and Gonzalez, 1996). These ratios in the n-3 Def group were slightly Fatty acid methyl esters from 10:0 to 24:1n-9 were analyzed. ...
Docosahexaenoic acid (DHA), an n-3 fatty acid, is rapidlydeposited during the period of rapid brain development. The influence of n-3fatty acid deficiency on learning performance in adult rats over twogenerations was investigated. Rats were fed either an n-3 fatty acid-adequate(n-3 Adq) or -deficient (n-3 Def) diet for three generations (F1-F3). Levelsof total brain n-3 fatty acids were reduced in the n-3 Def group by 83 and 87%in the F2 and F3 generations, respectively. In the Morris water maze, the n-3Def group showed a longer escape latency and delayed acquisition of this taskcompared with the n-3 Adq group in both generations. The acquisition andmemory levels of the n-3 Def group in the F3 generation seemed to be lowerthan that of the F2 generation. The 22:5n-6/22:6n-3 ratio in the frontalcortex and dams' milk was markedly increased in the n-3 Def group, and thisratio was significantly higher in the F3 generation compared with the F2generation. These results suggest that learning and cognitive behavior arerelated to brain DHA status, which, in turn, is related to the levels of themilk/dietary n-3 fatty acids.
... The primary source of forebrain 5-HT is the dorsal raphe nucleus (Berger et al., 2009;Jones et al., 2009). Pre-clinical studies have shown that stimulation of 5-HT neurons in the dorsal raphe nucleus induces anxiolytic and antidepressant-like behaviors (Glaser, 1987;Andrews et al., 1994;File & Gonzalez, 1996). On the other hand, inhibition of the neuronal activity of this region results in depressive-like behaviors which are accompanied by a reduction in 5-HT release from the dorsal raphe nucleus (Andrews et al., 1994). ...
Recreational and chronic cannabis use has been associated with a range of acute and chronic effects including; anti‐nociceptive actions, anxiety, depression, psychotic symptoms and neurocognitive impairments. The mechanisms underlying cannabinoid‐based drugs effects are not fully known but given the neuro‐modulatory functions of the endocannabinoid system, it seems likely that agonistic activity at the cannabinoid type‐1 receptors (CB1) might modulate the functions of other neurotransmitter systems. The present review has summarized the currently available pre‐clinical and clinical data on the interactions of CB1 and cannabinoid type‐2 receptors (CB2) with the central neurotransmitters; dopamine, serotonin, noradrenaline, GABA, glutamate and opioids. Acute and chronic exposures to cannabinoids exert pharmacological alterations in the mammalian brain that have profound implications for our understanding of the neuropharmacology of cannabinoid‐based drugs and their effects on mental health and the brain. A recent emergence uses of cannabis for medical purpose together with legalization and decriminalization of cannabis and increasing use of highly potent synthetic cannabinoids raise a growing concern over the effects of cannabinoids and their interaction with other neurotransmitters on physical and mental health.
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... EPM EPM test was implicated on day 8 of the treatment period after Aβ 25-35 injection and 1-week PHL treatment with an aim to assess their effects on novel stimulation-kindled fear/anxiety and also on the exploratory propensity of rats (File and Gonzalez 1996;Harkany et al. 1999). The major parameter considered for analyzing anxiety behavior was the ratio of the time spent in open arms to that spent in the closed arms. ...
Alzheimer’s disease (AD) is the leading neurodegenerative disorder with extracellular senile plaques and neurofibrillary tangles as the major hallmarks. The objective was to evaluate the effect of phloretin in a chronic model of sporadic AD by injecting aggregated form of Aβ25-35 peptide sequence intracerebroventricularly (icv) in Wistar rats. To achieve this, male Wistar rats were injected with aggregated Aβ25-35 peptide icv, followed by 21 days phloretin (2.5 mg/kg, 5 mg/kg) administration after recovery period. Barnes maze and elevated plus maze along with the biochemical estimation of antioxidant enzymes activities were conducted. The hippocampus region of the rat brains were stained with Congo red and Nissl stain. TNF-α was estimated in the brain homogenates using the ELISA assay. In this study, phloretin improved the spatial memory formation and retention in Barnes maze test. Additionally, phloretin alleviated the antioxidant defense biomarkers and thereby reduced oxidative stress, decreased TNF-α-mediated neuroinflammation. Furthermore, phloretin treatment showed decreased amyloid beta accumulation in the CA1 region and less number of pyknotic nuclei in the dentate gyrus of the Aβ25-35-injected rat brains. The above experimental findings evinced the promising role of phloretin in Aβ25-35-injected rats and which further envisage its potential to be explored in the treatment of AD.
... This is supported by our findings that nicotine enhances the inherent genotype difference in the MB test and that nicotine-induced inward currents in DRN neurons of Lypd6 KO mice had markedly greater amplitude compared to WT controls. The DRN provides the predominant serotonergic input to the forebrain and has been directly linked to anxiety (Cheeta et al., 2001a;File and Gonzalez, 1996;Higgins et al., 1988). In the DRN, nicotine activates the majority of 5-HT neurons by acting directly on post-synaptic α4β2 and α7 nAChRs, but also via presynaptic α4β2 located on glutamatergic neurons that mediate glutamate-dependent excitation of 5-HT DRN neurons (Galindo-Charles et al., 2008;Garduño et al., 2012). ...
... More consistent data support the use of Risperidone and Aripiprazole (the two approved treatments for ASD) (McCracken et al., 2002 andMcDougle et al., 2005), which are antagonists at multiple monoamine receptors, including the serotonin receptor 5-HT2A. Drugs targeting serotonin receptors, particularly 5-HT1A and 5-HT2A, have shown promise for increasing social interaction or decreasing cognitive rigidity (File et al., 1996, Edwards et al., 2006, Boulougouris and Robbins, 2010, Gould et al., 2011and Amodeo et al., 2014. Most of this work has been conducted in animal models with limited research in humans. ...
Language encompasses an ability to acquire and integrate complex cognitive systems in order to communicate with others, and inherited factors are thought to play a key role in modulating these emergent skills. In recent years, the role of genetics in language has gained focus and attention, based on accumulating empirical knowledge about the genes, proteins, and cellular machinery involved. In particular, disruption to various mechanisms has been shown to relate to impairments in language -- as seen in neurodevelopmental disorders such as autism, dyslexia and SLI. Mouse models can serve as a useful tool in studying the genetic modulators of related neural circuitry. The central over-arching aim of the current series of studies was to examine behavioral and neuroanatomic profiles of transgenic mice modeled on several established neurodevelopmental disorders (NDDs). We focused on five transgenic murine preparations exhibiting mutations derived from NDD populations characterized by atypical language. These include NDDs with language disability as a core feature of the disorder (e.g., specific language impairment (SLI), dyslexia), or as a sub-type (i.e., only some individuals affected; autism spectrum disorders (ASD)). The transgenic models assessed include: (1) Cntnap2 knock-out (KO; implicated in ASD and SLI); (2) Dyx1c1 conditional forebrain KO (implicated in dyslexia); (3) Ts2-neo model (a mutation associated with ASD); (4) Dcdc2 KO (implicated in dyslexia); and (5) Shank3b KO (associated with ASD). Using these models, we assessed specific links between: (a) genetically driven alterations in neurodevelopment; and (b) anomalies in fundamental non-verbal behaviors subserving aspects of language-learning. Our novel behavioral paradigms were able to tap “intermediate” language-related behavioral phenotypes in mice. Amanda Rose Rendall – University of Connecticut, 2017 Measures included acoustic processing of rapid and complex stimuli, visual motion perception, sensorimotor functions, social/communicative interactions, and working memory. We also quantified gross neuroanatomy to assess whether neural anomalies correlate with any atypical behaviors. Cumulative findings provide insight about the role of genes critical in the polygenic developmental cascade supporting emergent language, as well as the consequences of disruption to those pathways. Ongoing research may promote enhanced early screening of infants, as well as individualized treatment techniques for neurodevelopmental disorders that include language and communicative impairments.
... Based on the design of File and Gonzalez (50,51), the maze consisted of 2 opposite closed arms (30 Â 5 cm) enclosed by walls (15 cm in height) and 2 opposite open arms (also 30 Â 5 cm, without edges), forming a plus shape. ...
Methylmalonic acid (MMA) accumulates in tissues in methylmalonic acidemia, a heterogeneous group of inherited childhood diseases characterized by neurological dysfunction, oxidative stress and neuroinflammation; it is associated with degeneration of striatal neurons and cerebral cortical atrophy. It is presently unknown, however, whether transient exposure to MMA in the neonatal period is sufficient to trigger inflammatory and apoptotic processes that lead to brain structural damage. Here, newborn mice were given a single intracerebroventricular dose of MMA at 12 hours after birth. Maze testing of 21- and 40-day-old mice showed that MMA-injected animals exhibited deficit in the working memory test but not in the reference test. MMA-injected mice showed increased levels of the reactive oxygen species marker 20,70-dichlorofluorescein diacetate, tumor necrosis factor, interleukin-1b, caspases 1, 3, and 8, and increased acetylcholinesterase activity in the cortex, hippocampus and striatum. This was associated with increased astrocyte and microglial immunoreactivity in all brain regions. These findings suggest that transient exposure to MMA may alter the redox state and cause neuroinflammatory/apoptotic processes and glial activation during critical periods of brain development. Similar processes may underlie brain dysfunction and cognitive impairment in patients with methylmalonic acidemia. © 2017 American Association of Neuropathologists, Inc. All rights reserved.
... Thus, while traditional views on 5-HT and anxiety would suggest a post-synaptic locus (i.e., reduction in 5-HT transmission), empirical support must be obtained through studies on the effects of direct antagonist application to sites such as the raphe nuclei and hippocampus. In this context, it is worth noting that anxiolyticlike effects have been reported in several rat models following intrahippocampal injection of the mixed 5-HT 1A antagonist/ßblocker tertatolol (103), while hippocampal and amygdaloid injections of 8-OH-DPAT have been found to enhance anxiety (104,105). However, the fact that 5-HT 1A receptor manipulations would appear to have more consistent effects in mouse (vs rat) models of anxiety (e.g., 5,8,[100][101][102] and that a clear species difference exists in 5-HT 1A receptor-mediated physiological responses (e.g., 8-OH-DPAT-induced hypothermia: pre-synaptic in mouse but postsynaptic in rat, 106) would caution against over-interpretation of these findings. ...
In the field of anxiety research, animal models are used as screening tools in the search for compounds with therapeutic potential and as simulations for research on mechanisms underlying emotional behaviour. However, a solely pharmacological approach to the validation of such tests has resulted in distinct problems with their applicability to systems other than those involving the benzodiazepine/GABAA receptor complex. In this context, recent developments in our understanding of mammalian defensive behaviour have not only prompted the development of new models but also attempts to refine existing ones. The present review focuses on the application of ethological techniques to one of the most widely used animal models of anxiety, the elevated plus-maze paradigm. This fresh approach to an established test has revealed a hitherto unrecognized multidimensionality to plus-maze behaviour and, as it yields comprehensive behavioural profiles, has many advantages over conventional methodology. This assertion is supported by reference to recent work on the effects of diverse manipulations including psychosocial stress, benzodiazepines, GABA receptor ligands, neurosteroids, 5-HT1A receptor ligands, and panicolytic/panicogenic agents. On the basis of this review, it is suggested that other models of anxiety may well benefit from greater attention to behavioural detail
... The microinjection of LP-44 (5-HT 7 receptor agonist) into the ventral hippocampus significantly enhanced memory-dependent fear expression in the contextual fear conditioning test (Fig. 3b). Although LP-44 has low but not negligible affinity for 5-HT 1A receptors, it would not explain the enhancement of fear expression because the stimulation of 5-HT 1A receptors in the ventral hippocampus increased locomotor activity (File and Gonzalez, 1996), which could reduce the freezing rate. Therefore, it is highly likely that the 5-HT 7 receptor in the ventral hippocampus has a pivotal role in fear memory retrieval. ...
Background:
Patients with posttraumatic stress disorder or panic disorder are often troubled by inappropriate retrieval of fear memory. Moreover, these disorders are often comorbid with irritable bowel syndrome. The main aim of the present study is to elucidate the involvement of hippocampal serotonergic systems in fear memory retrieval and stress-induced defecation.
Methods and Results:
Microinjection of serotonin7 receptor antagonist, but not other serotonin receptor antagonists (serotonin 1A, 2A, 2C, 3, 4, and 6), into the rat ventral hippocampus significantly suppressed the expression of freezing behavior, an index of fear memory retrieval, and decreased the amount of feces, an index of stress-induced defecation, in the contextual fear conditioning test. Electrophysiological data indicated that the serotonin7 receptor agonist increased the frequency of action potentials in the ventral hippocampal CA3 pyramidal neuron via the activation of the hyperpolarization-activated nonselective cation current Ih. Moreover, in situ hybridization demonstrated that Htr7 mRNA was abundantly expressed in the CA3 compared with other subregions of the hippocampus and that these Htr7 mRNA-positive cells coexpressed hyperpolarization-activated cyclic nucleotide-gated channel 2 and 4 mRNAs, which are components of the Ih channel.
Conclusions:
These results indicated that the released serotonin activates the serotonin7 receptor in the CA3 ventral hippocampus subregion, enhances the sensitivity to inputs via hyperpolarization-activated cyclic nucleotide 2 and 4 channels, and thereby facilitates fear memory retrieval. The serotonin7 receptor might be a target of drug development for the treatment of mental disorders involving fear memory and gastrointestinal problems.
... Such stimuli include predator smells or dark, confined spaces (for people; rodents find bright, open spaces aversive). Although both forms of anxiety appear to rely on the amygdala and prefrontal cortex (Deacon et al. 2002, Gonzalez et al. 2000, Lacroix et al. 2000, Shah & Treit 2003, Shah et al. 2004, studies in rodents suggest that innate forms of anxiety also require an extended network of additional brain regions, including the hippocampus and bed nucleus of the stria terminals (Bannerman et al. 2003, Deacon et al. 2002, File & Gonzalez 1996, Kim et al. 2013, Kjelstrup et al. 2002. Consistent with these findings, we have found increased LFP coherence and spike-LFP phase locking between the mPFC and the hippocampus in mice exploring anxiety-provoking environments, such as the open field and the elevated plus maze, which both rely on open spaces to induce anxiety (Adhikari et al. 2010). ...
Long-range synchrony between distant brain regions accompanies multiple forms of behavior. This review compares and contrasts the methods by which long-range synchrony is evaluated in both humans and model animals. Three examples of behaviorally relevant long-range synchrony are discussed in detail: gamma-frequency synchrony during visual perception, hippocampal-prefrontal synchrony during working memory, and prefrontalamygdala synchrony during anxiety. Implications for circuit mechanism, translation, and clinical relevance are discussed. Expected final online publication date for the Annual Review of Neuroscience Volume 38 is July 08, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
... Farklı beyin yapılarının anksiyete ve korkunun farklı ölçütlerini modüle ettiği ve amigdalanın bazolateral çekirdeğinin fobik yanıtlara ve beklenen anksiyete oluşumuna katıldığı ileri sürülmektedir. 12,13 Fakat amigdala bazolateral çekirdeğinin anlık ve uzun süreli yaygınlaşmış anksiyete/korku bozukluğundaki rolü bilinmemektedir. ...
Objective: Amygdala plays a critical role in affect, is involved in anxiety disorders and anxiety related environmental fear conditioning. The aim of this study was to investigate the role of basolateral amygdala (BLA) in hereditary anxiety/fear behaviours and learned cog-nitive and affective anxiety/fear behaviours. Material and Methods: Wistar male rats were used in our study. Subjects were divided into two groups as sham (control) group and BLA lesion group. Rats were allowed to heal for two weeks after surgical procedure and were tested there-after. Effect of BLA on acquisition, storage and recalling of cognitive and affective fear behav-iours was evaluated using learning tests like passive avoidance test and unsigned Pavlov type fear conditioning. Results: In the passive avoidance test, immediately after and 48 hours after the shock, impairment was seen in freeze and avoidance from dark behaviors in rats with BLA le-sions compared to control rats. This finding indicates that acquisition and cognitive fear condi-tioning performance in memory was impaired. When the test in the shock applied environment (unsigned Pavlov type conditioning mechanism) was repeated, BLA lesion impaired conditional freeze; this finding indicates that lesion impairs acquisition and storage processes in affective fear conditioning. Conclusion: We suggest that BLA is involved in the expression of unconditional freeze memory and in establishing a relatinship between environmental clues and sensorial com-ponent of unconditional stimulus.
... Our data are consistent with studies of 5-HT 1A autoreceptor knockout mice, which exhibit increased fearful behavior (7). In addition, direct injection of a 5-HT 1A receptor agonist into the DRN has been reported to reduce anxiety in mice (42,43). Taken together with these results from rodent studies, our findings indicate that DRN presynaptic 5-HT 1A receptors play a key modulatory role in amygdala reactivity to fearful stimuli in humans. ...
Background:
The amygdala is a central node in the brain network that processes aversive emotions and is extensively innervated by dorsal raphe nucleus (DRN) serotonin (5-hydroxytryptamine [5-HT]) neurons. Alterations in DRN 5-HT1A receptor availability cause phenotypes characterized by fearful behavior in preclinical models. However, it is unknown whether 5-HT1A receptor availability is linked specifically to the processing of aversive emotions in humans or whether it modulates connectivity in brain networks involved in emotion processing. To answer this question, we investigated the relationship between DRN 5-HT1A receptor availability and amygdala reactivity to aversive emotion and functional connectivity within the amygdala-cortical network.
Methods:
We studied 15 healthy human participants who underwent positron emission tomography scanning with [(11)C]CUMI-101, a 5-HT1A partial agonist radioligand, and functional magnetic resonance imaging of brain responses during an incidental emotion processing task including happy, fearful, and neutral faces. Regional estimates of 5-HT1A receptor binding potential (nondisplaceable) were obtained by calculating total volumes of distribution for presynaptic DRN and amygdala. Connectivity between the amygdala and corticolimbic areas was assessed using psychophysiologic interaction analysis with the amygdala as the seed region.
Results:
Analysis of the fear versus neutral contrast revealed a significant negative correlation between amygdala response and DRN binding potential (nondisplaceable) (r = -.87, p < .001). Availability of DRN 5-HT1A receptors positively correlated with amygdala connectivity with middle frontal gyrus, anterior cingulate cortex, bilateral precuneus, and left supramarginal gyrus for fearful (relative to neutral) faces.
Conclusions:
Our data show that DRN 5-HT1A receptor availability is linked specifically to the processing of aversive emotions in the amygdala and the modulation of amygdala-cortical connectivity.
... For example, it has been reported that infusion of 5-HT 1A agonists into the DRN increased social interaction (SI), suggesting that the drug-induced increases in SI reflected decreases in anxiety (Higgins et al. 1992). Furthermore, the 5-HT 1A agonist, 8- OH-DPAT, has been acutely injected into restricted brain areas such as MRN and DRN resulting in an anxiolytic action (Andrews et al. 1994; De Almeida et al. 1998; File et al. 1996; Hogg et al. 1994). On the other hand, acute stimulation of the post-synaptic 5-HT 1A receptors in the dorsal HP results in an anxiogenic effect in the same tasks in which the knockouts behave abnormally (Andrews et al. 1994; File and Gonzalez 1996; File et al. 1996; Stefański et al. 1993). ...
Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in both disorders.
In this review, we examine the function of 5-HT1A receptor subpopulations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor versus heteroreceptor) and the temporal (developmental versus adult) roles of the endogenous 5-HT1A receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors.
It is difficult to unambiguously distinguish the effects of different populations of the 5-HT1A receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for the distinct roles of these populations in governing emotion-related behavior is emerging.
There is strong and growing evidence for a functional dissociation between auto- and heteroreceptor populations in mediating anxiety and depressive-like behaviors, respectively. Furthermore, while it is well established that 5-HT1A receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT1A heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects.
... Based on the design of File and Gonzalez [37] the maze consisted of two opposite closed arms (30 cm x 5 cm) enclosed with walls (15 cm in height) and two opposite open arms (also 30 cm x 5 cm, without edges) forming a plus shape. The whole apparatus had a central arena (5 cm x 5 cm) and was elevated to 80 cm above the floor by a tripod. ...
Glutaric aciduria type I (GA-I) is characterized by accumulation of glutaric acid (GA) and neurological symptoms, such as cognitive impairment. Although this disease is related to oxidative stress and inflammation, it is not known whether these processes facilitate the memory impairment. Our objective was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS) in spatial memory test, antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. We also evaluated the effect of N-acetylcysteine (NAC) on theses markers.
Rat pups were injected with GA (5umol g of body weight-1, subcutaneously; twice per day; from 5th to 28th day of life), and were supplemented with NAC (150mg/kg/day; intragastric gavage; for the same period). LPS (2mg/kg; E.coli 055 B5) or vehicle (saline 0.9%) was injected intraperitoneally, once per day, from 25th to 28th day of life. Oxidative stress and inflammatory biomarkers as well as hippocampal volume were assessed.
GA caused spatial learning deficit in the Barnes maze and LPS potentiated this effect. GA and LPS increased TNF-α and IL-1β levels. The co-administration of these compounds potentiated the increase of IL-1β levels but not TNF-α levels in the hippocampus. GA and LPS increased TBARS (thiobarbituric acid-reactive substance) content, reduced antioxidant defenses and inhibited Na+, K+-ATPase activity. GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. The hippocampal volume did not change after GA or LPS administration. NAC protected against impairment of spatial learning and increase of cytokines levels. NAC Also protected against inhibition of Na+,K+-ATPase activity and oxidative markers.
These results suggest that inflammatory and oxidative markers may underlie at least in part of the neuropathology of GA-I in this model. Thus, NAC could represent a possible adjuvant therapy in treatment of children with GA-I.
... One distal amygdalar projection target implicated in anxietyrelated behaviors is the ventral hippocampus (vHPC; File and Gonzalez, 1996;McHugh et al., 2004;Richardson et al., 2004). The vHPC shares robust reciprocal connections with the basolateral nucleus of the amygdala (BLA; O'Donnell and Grace, 1995;Pikkarainen et al., 1999). ...
The basolateral amygdala (BLA) and ventral hippocampus (vHPC) have both been implicated in mediating anxiety-related behaviors, but the functional contribution of BLA inputs to the vHPC has never been directly investigated. Here we show that activation of BLA-vHPC synapses acutely and robustly increased anxiety-related behaviors, while inhibition of BLA-vHPC synapses decreased anxiety-related behaviors. We combined optogenetic approaches with in vivo pharmacological manipulations and ex vivo whole-cell patch-clamp recordings to dissect the local circuit mechanisms, demonstrating that activation of BLA terminals in the vHPC provided monosynaptic, glutamatergic inputs to vHPC pyramidal neurons. Furthermore, BLA inputs exerted polysynaptic, inhibitory effects mediated by local interneurons in the vHPC that may serve to balance the circuit locally. These data establish a role for BLA-vHPC synapses in bidirectionally controlling anxiety-related behaviors in an immediate, yet reversible, manner and a model for the local circuit mechanism of BLA inputs in the vHPC.
... There is growing evidence that different animal tests are measuring different types or states of anxiety, and principal component analysis has shown that measures derived from different animal tests reflect different underlying factors (File, 1992). There is also evidence of quite distinctive roles for GABA and 5-HT in the control of behavior in the social interaction and elevated plus-maze tests (File & Gonzalez, 1996; 352 This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. ...
Dorsal hippocampal cholinergic modulation of behavior in different tests of anxiety was investigated by direct injection of the muscarinic M₁ and M₂ receptor antagonists, pirenzepine and gallamine, and the nicotinic receptor antagonist mecamylamine. In the social interaction test, the anxiogenic effect of pirenzepine (30–100 ng) provided evidence for a tonic cholinergic anxiolytic action mediated by postsynaptic M₁ receptors. The anxiogenic action of mecamylamine (30 and 100 ng) was most likely mediated by its action of presynaptic nicotinic receptors to reduce acetylcholine release. Gallamine (10–1,000 ng) was without effect, suggesting that M₂ receptors in this brain region do not play a significant role in this behavioral test. On Trial 1 in the elevated plus-maze, the receptor antagonists were without any effect, but in those with a previous 5-min experience of the plus-maze pirenzepine and mecamylamine had anxiogenic effects in the dose range of 30–300 ng; gallamine (100 and 300 ng) was without significant effect. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
... Initially, the animals were put on the crossroad of the maze in a similar way (File and Gonzalez 1996). The animals could explore the maze during 5 min. ...
... Indeed, serotonin levels or stimulation of various serotoninergic receptors have been positively correlated with hippocampal neurogenesis (Banasr et al., 2004;Daszuta, 1999, 2000;Lucas et al., 2007;Radley and Jacobs, 2002;Santarelli et al., 2003). Finally, heterogeneous expression or function of some of those receptors within the dorsoventral axis of the hippocampus has been described (Adams and van den Buuse, 2011;Alves et al., 2004;File and Gonzalez, 1996;Lin et al., 2012) which could further participate in the differential effects of fluoxetine we observed. ...
The hippocampus is involved in both cognitive and emotional processing; these different functions are topographically distributed along its septo-temporal axis, the dorsal (septal) hippocampus being preferentially involved in cognitive processes such as learning and memory while the ventral (temporal) hippocampus participates in emotional regulation and anxiety-related behaviors. Newborn hippocampal neurons become functionally integrated into hippocampal networks and are likely to contribute to hippocampal functions, but whether their regulation and function are homogenous throughout this axis is not clear. Here we investigate changes in cell proliferation and neurogenesis along the septo-temporal axis of the hippocampus induced by the Unpredictable Chronic Mild Stress model of depression (UCMS), chronic fluoxetine treatment and enriched environment. Mice were either subjected to UCMS, standard housing or enriched environment. Stress-exposed mice were treated daily with fluoxetine (10 mg/kg) or vehicle. Effects of UCMS regimen, fluoxetine treatment and enrichment were assessed by physical measures and behavioral testing. Quantitative changes in cell proliferation and neurogenesis were assessed by immunohistochemistry using BrdU labeling. Results indicate that UCMS decreased cell proliferation and neurogenesis preferentially in the ventral hippocampus, an effect that was reversed by fluoxetine treatment. Environmental enrichment on the other hand increased cell proliferation in both divisions but promoted neurogenesis only in the dorsal hippocampus. These results indicate that environmental factors can differentially regulate neurogenesis in a region-specific manner. This may possibly underlie heterogeneous function of newborn neurons along the septo-temporal axis of the hippocampus and have functional significance as to their implication in stress related disorders and memory processes.
... Local injection of an agonist for 5-HT 1A receptors, flesinoxon, into the dorsal raphe attenuates social defeat in animals, while WAY100635, an antagonist for 5-HT 1A receptors, injected into the dorsal raphe enhances defeat-related conditioning (61). Similarly, injection of the 5-HT 1A receptor agonist 8-OH-DPAT into the dorsal raphe alleviated anxiety of rats when examined with a maze task (63) and reduced the efficacy of fear conditioning using inescapable shock (64,65). Thus, the ability of aripiprazole to reverse anxiety-like behavior in mice with ethanol physical dependence may involve 5-HT 1A receptors. ...
In the present study, we investigated the effect of aripiprazole, a dopamine system stabilizer, on ethanol-induced psychological and physiological dependence and anxiety-like behavior. First we determined the effect of aripiprazole, a dopamine system stabilizer, on the development and expression of ethanol-induced place preference. Both the development and expression of ethanol-induced place preference was significantly suppressed by treatment of aripiprazole. Next, the withdrawal score gradually increased with increasing duration after the withdrawal from ethanol for 6 days in vehicle-treated mice and the maximal score was observed 10 h after the ethanol withdrawal. Aripiprazole caused no changes in the withdrawal score as compared to vehicle-treated mice. Under these conditions we investigated the effect of aripiprazole on the anxiety-like behavior of ethanol physical dependent mice, which were animals subjected to ethanol vapor for 6 days. The significant decrease of time spent in the open arms and number of open arm entries characterize the anxiety-like behavior in ethanol physical dependent mice, compared to control mice. These decreases were reversed by treatment of aripiprazole, which were inhibited by WAY100635, a serotonin 5-HT(1A) receptor antagonist. The present findings suggest that aripiprazole was efficient for reversing ethanol-induced place preference and anxiety-like behavior.
... AAV2-NaGlu vector-treated mice showing normal behavior in the elevated plus-maze at 18 and 34 weeks of age also showed high NaGlu activity at 38 weeks of age, although the enzyme was primarily located in the injected hemisphere. Consistent with previous reports, this observation suggests that behavioral improvement in the elevated plus-maze may not require enzyme delivery to brain hemispheres (Graeff et al., 1993;File and Gonzalez, 1996). ...
Sanfilippo syndrome is a mucopolysaccharidosis (MPS) caused by a lysosomal enzyme defect interrupting the degradation pathway of heparan sulfates. Affected children develop hyperactivity, aggressiveness, delayed development, and severe neuropathology. We observed relevant behaviors in the mouse model of Sanfilippo syndrome type B (MPSIIIB), in which the gene coding for alpha-N-acetylglucosaminidase (NaGlu) is invalidated. We addressed the feasibility of gene therapy in these animals. Vectors derived from adeno-associated virus serotype 2 (AAV2) or 5 (AAV5) coding for NaGlu were injected at a single site in the putamen of 45 6-week-old MPSIIIB mice. Normal behavior was observed in treated mice. High NaGlu activity, far above physiological levels, was measured in the brain and persisted at 38 weeks of age. NaGlu immunoreactivity was detected in neuron intracellular organelles, including lysosomes. Enzyme activity spread beyond vector diffusion areas. Delivery to the entire brain was reproducibly obtained with both vector types. NaGlu activity was higher and distribution was broader with AAV5-NaGlu than with AAV2-NaGlu vectors. The compensatory increase in the activity of various lysosomal enzymes was improved. The accumulation of gangliosides GM2 and GM3 present before treatment and possibly participating in neuropathology was reversed. Characteristic vacuolations in microglia, perivascular cells, and neurons, which were prominent before the age of treatment, disappeared in areas in which NaGlu was present. However, improvement was only partial in some animals, in contrast to high NaGlu activity. These results indicate that NaGlu delivery from intracerebral sources has the capacity to alleviate most disease manifestations in the MPSIIIB mouse model.
... Understanding how specific raphe circuits and neuron populations control particular behaviors requires a mechanistic description at the cellular and circuit level. Many investigators have proposed that the different subfields of DR and MR have differential roles in terms of mediating stress, anxiety and depression (Adell et al., 1997;Andrade and Graeff, 2001;Andrade et al., 1999;Andrews et al., 1997;Andrews et al., 1994;File and Gonzalez, 1996;Gonzalez and File, 1997;Gonzalez et al., 1998;Graeff et al., 1996;Lowry, 2002). Raphe circuits involve direct modulation of the HPA axis as well as indirectly mediated influences orchestrated by raphe projections to other limbic structures (e.g., the hippocampus, amygdala, and medial prefrontal cortex) and brainstem areas that regulate the autonomic nervous system. ...
The median (MR) and dorsal raphe (DR) nuclei contain the majority of the 5-hydroxytryptamine (5-HT, serotonin) neurons that project to limbic forebrain regions, are important in regulating homeostatic functions and are implicated in the etiology and treatment of mood disorders and schizophrenia. The primary synaptic inputs within and to the raphe are glutamatergic and GABAergic. The DR is divided into three subfields, i.e., ventromedial (vmDR), lateral wings (lwDR) and dorsomedial (dmDR). Our previous work shows that cell characteristics of 5-HT neurons and the magnitude of the 5-HT(1A) and 5-HT(1B) receptor-mediated responses in the vmDR and MR are not the same. We extend these observations to examine the electrophysiological properties across all four raphe subfields in both 5-HT and non-5-HT neurons. The neurochemical topography of glutamatergic and GABAergic cell bodies and nerve terminals were identified using immunohistochemistry and the morphology of the 5-HT neurons was measured. Although 5-HT neurons possessed similar physiological properties, important differences existed between subfields. Non-5-HT neurons were indistinguishable from 5-HT neurons. GABA neurons were distributed throughout the raphe, usually in areas devoid of 5-HT neurons. Although GABAergic synaptic innervation was dense throughout the raphe (immunohistochemical analysis of the GABA transporters GAT1 and GAT3), their distributions differed. Glutamate neurons, as defined by vGlut3 anti-bodies, were intermixed and co-localized with 5-HT neurons within all raphe subfields. Finally, the dendritic arbor of the 5-HT neurons was distinct between subfields. Previous studies regard 5-HT neurons as a homogenous population. Our data support a model of the raphe as an area composed of functionally distinct subpopulations of 5-HT and non-5-HT neurons, in part delineated by subfield. Understanding the interaction of the cell properties of the neurons in concert with their morphology, local distribution of GABA and glutamate neurons and their synaptic input, reveals a more complicated and heterogeneous raphe. These results provide an important foundation for understanding how specific subfields modulate behavior and for defining which aspects of the circuitry are altered during the etiology of psychological disorders.
Changes in 5-HT1A receptor (5-HT1AR)-mediated neurotransmission in the hippocampus have been associated with anxiety, depression and in the mode of action of antidepressant drugs. It has been commonly accepted that whereas the dorsal pole of the hippocampus (DH) is involved in cognitive processing, the ventral pole (VH) is associated with emotional regulation. However, to date, only a few studies have directly addressed the role played by VH 5-HT1ARs in anxiety and panic processing, and their results are conflicting. Here we report that intra-VH administration of the 5-HT1A receptor agonist 8-OH-DPAT, the endogenous agonist serotonin (5-HT), or the standard anxiolytic benzodiazepine midazolam impaired the acquisition of inhibitory avoidance in the elevated T-maze (ETM) of male Wistar rats, indicating an anxiolytic effect. Conversely, local injection of the 5-HT1AR antagonist WAY-100635 caused the opposite effect. These results were equally found in the Vogel conflict test. None of these drugs interfered with locomotor activity in the open-field test, nor did they alter the expression of the escape response in the ETM, a defensive behavior associated with panic. Pre-injection of a sub-effective dose of WAY-100635 in the VH blocked the anxiolytic effect of 5-HT or 8-OH-DPAT in the Vogel test, confirming the involvement of 5-HT1AR for this behavioral effect. The effect in this test was anxiety-selective as none of the drugs affected water consumption or nociception. In conclusion, our results suggest that 5-HT1ARs in the VH play a tonic inhibitory role in anxiety processing. These receptors, however, are not involved in the regulation of panic-related escape behavior.
The extent to which rats express anxiety-like behavior on the elevated plus-maze (EPM) depends on their previous maze experience. Open-arm avoidance develops in maze-experienced rats, and is often accompanied by a diminished anxiolytic response to benzodiazepines. Regions of the dorsal raphe nucleus (DRN) were examined in male Sprague-Dawley rats using c-Fos and serotonin immunohistochemistry following a single exposure, a second exposure or no exposure to the EPM. We then examined the effect of the benzodiazepine anxiolytic chlordiazepoxide (CDP, 5 mg/kg) on EPM behavior and DRN neural activity. Enhanced open-arm avoidance was evident on the second EPM trial in both experiments. The observed pattern of c-Fos expression suggests that the first exposure to the maze activates serotonin cells in the rostral and dorsal regions of the DRN and that only the dorsal subregion is activated by a second exposure. CDP increased open-arm exploration during the first trial, which corresponded to decreased 5-hydroxytryptamine (5-HT) activity in the rostral and ventral subregions of the DRN. However, 5-HT activity in the DRN was reduced in rats on the second maze trial compared with the first trial, when CDP had no effect on open-arm exploration. These results suggest that open-arm avoidance in maze-experienced rats can be characterized as a coping response that is mediated by specific populations of 5-HT neurons in the DRN.
Epidemiological studies of mental disorders show that roughly half of the population in the USA meets criteria for one or more of such disorders in their lifetimes, and nearly a quarter in a given year has a psychiatric disorder. Most of the first psychiatric medications, including antidepressant and antipsychotic drugs, were serendipitously discovered, and their molecular and cellular mechanisms of action are just starting to be explored. At present, only a handful of neurotransmitter systems are actually targeted by therapeutic drugs, which represents a major bottleneck that hampers the development of new central nervous system-active drugs. In this chapter, we review some of the recent advances in understanding the neurobiology of psychiatric disorders, current work on the basic and clinical aspects of drugs used for their treatment, and major concepts related to new targets in molecular psychiatry research.
While anxiogenic stimuli activate neurons in the raphe and lead to serotonin release in limbic forebrain targets, panicogenic stimuli do not necessarily do so. For example, escape performance in an elevated T-maze does not increase c-Fos-like immunoreactivity in the raphe. Nonetheless, the observation of a panicolytic role of serotonin in the PAG and an anxiogenic role in the amygdala and hippocampus suggests that the raphe is not a homogeneous structure. In fact, the dorsal raphe can be divided at least into six subregions based on cytoarchitecture and distribution of serotonergic neurons. These comprise the rostral (DRr), dorsal (DRD), ventral (DRV), lateral wing (lwDR), caudal (DRC), and interfascicular (DRI) portions (Fig. 5.1). Among those, the rostral, ventral, and interfascicular subregions play little role in the control of defense responses, and discussion of their functions can be found elsewhere. Here, we will discuss evidence for a role of the DRD, lwDR and DRC in anxiety and fear.
The first reports on the role of the serotonergic system in the control of defensive behavior in animal models date from the 1970s. Robichaud and Sledge [1] demonstrated that dl-para-chloropheynalainine (dl-pCPA), a serotonin synthesis inhibitor, releases punished behavior. Shortly after that, Graeff and Schoenfeld [2, 3] demonstrated that metisergide, lysergic acid, and bromolysergic acid (non-selective antagonists at 5-HT receptors) produce similar effects, while the non-selective agonist α-methyltryptamine increased the effect of punishment.
Two structures have been proposed as central in the control of anxiety-like responses, the basolateral amygdala [1] and the ventral hippocampus [2]; in addition, great attention is being given recently in the role of the lateral habenula [3–5] and cingulate cortex [6–8] in this process.
Serotonin (5-HT) plays an important role in the modulation of behavior across animal species. The serotonin 1A receptor (Htr1a) is an inhibitory G-protein coupled receptor that is expressed both on serotonin and non-serotonin neurons in mammals. Mice lacking Htr1a show increased anxiety behavior suggesting that its activation by serotonin has an anxiolytic effect. This outcome can be mediated by either Htr1a population present on serotonin (auto-receptor) or non-serotonin neurons (hetero-receptor), or both. In addition, both transgenic and pharmacological studies have shown that serotonin acts on Htr1a during development to modulate anxiety in adulthood, demonstrating a function for this receptor in the maturation of anxiety circuits in the brain. However, previous studies have been equivocal about which Htr1a population modulates anxiety behavior, with some studies showing a role of Htr1a hetero-receptor and others implicating the auto-receptor. In particular, cell-type specific rescue and suppression of Htr1a expression in either forebrain principal neurons or brainstem serotonin neurons reached opposite conclusions about the role of the two populations in the anxiety phenotype of the knockout. One interpretation of these apparently contradictory findings is that the modulating role of these two populations depends on each other. Here we use a novel Cre-dependent inducible allele of Htr1a in mice to show that expression of Htr1a in cortical principal neurons is sufficient to modulate anxiety. Together with previous findings, these results support a hetero/auto-receptor interaction model for Htr1a function in anxiety.
Lead (Pb) exposure during development can produce neurological deficits. In this study, the effect of Pb exposure during neonatal development via lactation on anxiety of brain function was investigated. Long-Evans strain rats were raised through two generations. At the birth of the second generation, the dams were subdivided into two groups and supplied drinking water containing either Pb (Pb-treated group) or sodium (Na, Control group) acetate until weaning. Rats were sacrificed at 3 (weaning) and 11 weeks (maturity) for brain Pb and fatty acid analysis. Motor activity and elevated plus maze tests were initiated at 9 weeks. The brains in the Pb-treated group at weaning and maturity contained 148698 and ng Pb/g, respectively The control group showed the background level of Pb ( Pb/g) in both ages. The alterations in brain fatty acid composition induced by Pb exposure were more evident in 3 wks old than 11 wks old. For example, in 3 wks old, the percentages of , and were decreased in the Pb-treated group with an increase in In motor activity test, there was a tendency of hyperactivity in the Pb-treated group compared with the control group but the difference was not significant. In elevated plus maze test, the Pb-treated group showed fewer numbers of visits to the open arms (P < 0.05), indicating that Pb exposure may lead to anxiogenic effect.
Due to the fish-specific genome duplication event (~320-350 mya), some genes which code for serotonin proteins were duplicated in teleosts; this duplication event was preceded by a reorganization of the serotonergic system, with the appearance of the raphe nuclei (dependent on the isthmus organizer) and prosencephalic nuclei, including the paraventricular and pretectal complexes. With the appearance of amniotes, duplicated genes were lost, and the serotonergic system was reduced to a more complex raphe system. From a comparative point of view, then, the serotonergic system of zebrafish and that of mammals shows many important differences. However, many different behavioral functions of serotonin, as well as the effects of drugs which affect the serotonergic system, seem to be conserved among species. For example, in both zebrafish and rodents acute serotonin reuptake inhibitors (SSRIs) seem to increase anxiety-like behavior, while chronic SSRIs decrease it; drugs which act at the 5-HT1A receptor seem to decrease anxiety-like behavior in both zebrafish and rodents. In this article, we will expose this paradox, reviewing the chemical neuroanatomy of the zebrafish serotonergic system, followed by an analysis of the role of serotonin in zebrafish fear/anxiety, stress, aggression and the effects of psychedelic drugs.
The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in different regions of the brain and is associated with cognitive function as well as anxiety. Agonists and positive allosteric modulators (PAMs) of the α7 subtype of nAChRs have been shown to improve cognition. Previously nicotine, which activates both α7 and non-α7 subtypes of nAChRs, has been shown to have an anxiogenic effect in behavioral tests. In this study, we compared the effects of the α7-selective agonist (PNU-282987) and PAM (PNU-120596) in a variety of behavioral tests in Sprague Dawley rats to look at their effects on learning and memory as well as anxiety. We found that neither PNU-282987 nor PNU-120596 improved spatial-learning or episodic memory by themselves. However when cognitive impairment was induced in the rats with scopolamine (1 mg/kg), both PNU-120596 and PNU-282987 were able to reverse this memory impairment and restore it back to normal levels. While PNU-120596 reversed the scopolamine-induced cognitive impairment, it did not have any adverse effect on anxiety. PNU-282987 on the other hand displayed an increase in anxiety-like behavior at a higher dose (10 mg/kg) that was significantly reduced by the serotonin 5-HT(1a) receptor antagonist WAY-100135. However the α7 receptor antagonist methyllycaconitine was unable to reverse these anxiety-like effects seen with PNU-282987. These results suggest that α7 nAChR PAMs are pharmacologically advantageous over agonists, and should be considered for further development as therapeutic drugs targeting the α7 receptors.
Rationale: Smokers frequently report that they obtain anxiety-reducing (anxiolytic) effects from smoking, and this may be one factor
which contributes to nicotine dependence. Objective: The aim of this study was to investigate the role of the dorsal raphé nucleus (DRN) in mediating the acute anxiolytic effect
of nicotine, the development of tolerance to this effect and the anxiogenic response observed on withdrawal from chronic nicotine. Methods: The social interaction test of anxiety was used to investigate the effects of a range of doses of (-)-nicotine (2.5–4000ng)
following DRN infusion, and whether co-administration of the specific 5-HT1A receptor antagonist WAY100635 could antagonise the anxiolytic action of nicotine. We then examined the effects of intra-DRN
nicotine (2.5–7ng) following six daily injections of subcutaneous (s.c.) (-)-nicotine (0.1mg/kg). Finally, we examined whether
s.c. or intra-DRN (-)-nicotine could antagonise the anxiogenic response seen 72h after the termination of 7days of nicotine
treatment. Results: Acute nicotine administration into the DRN produced dose-related effects: low doses (2.5–10ng) induced an anxiolytic effect,
intermediate doses were behaviourally silent (100–1000ng), and an anxiogenic effect was seen following administration of
a high dose (4µg). The anxiolytic effect of (-)-nicotine (5ng) was reversed by co-administration of a behaviourally inactive
dose of WAY100635 (200ng). Following 6days of treatment with s.c. 0.1mg/kg per day (-)-nicotine, tolerance developed to
its anxiolytic action in the DRN. Rats withdrawn for 72h following this chronic treatment showed an anxiogenic response which
was reversed by (-)-nicotine injected s.c. (0.1mg/kg) or into the DRN (5ng). Conclusions: The present findings therefore suggest that the DRN plays an important role in mediating the acute effects of nicotine on
anxiety, as measured in the social interaction test, and that the anxiolytic effect is mediated by activation of somatodendritic
5-HT1A autoreceptors. The DRN is also concerned with mediating the development of tolerance to nicotine's anxiolytic effects and
because there is an anxiogenic response 72h after withdrawal from chronic nicotine, this suggests that an oppositional, compensatory
mechanism is mediating the tolerance.
Although Creatine (Cr) and Phosphocreatine (PCr) systems play a key role in cellular energy and energy transport in neuronal cells, its implications for learning and memory are still controversial. Thus, we decided to investigate the involvement of cAMP-dependent protein kinase A (PKA), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and cAMP responsive element binding protein (CREB) in the spatial consolidation after an intrahippocampal injection of Cr. Statistical analysis revealed that Cr (2.5 nmol/hippocampus) (post-training) decreased the latency for escape and the mean number of errors on Barnes maze test. Post-training co-administration of the PKA inhibitor (H-89 25 ρmol/hippocampus) did not alter the facilitatory effect of Cr in this memory test. On the other hand, Cr-induced spatial retention was reverted by co-administration of the CaMKII inhibitor (STO-609 5 nmol/hippocampus). Neurochemical analysis revealed that intrahippocampal injection of Cr, when analyzed after 30 min rather than after 3 h, increased the levels of pCREB and pCaMKII but not pPKA levels. Statistical analysis also revealed that the post-training co-administration of STO-609 but not H-89 reversed the increase of pCREB levels induced by Cr. The results presented in this report suggest that intracellular CaMKII/CREB pathway plays a key role in the Cr-induced spatial retention. Thus, it is plausible to propose that Cr plays a putative role as a neuromodulator in the brain, and that at least some of its effects may be mediated by intracellular CaMKII/CREB pathway.
1.1. Different animal tests model different anxiety disorders. Thus, the social interaction test is a model of generalised anxiety disorder, plus-maze Trial 1 models elements of panic disorder and Trial 2 in the elevated plus-maze is a model of specific phobia.2.2. Studies of the neuroanatomical and neurochemical pathways controlling behaviour in these different tests provides information on the neurobiological mechanisms modulating anxiety disorders.3.3. In the social interaction test, nicotine and 8-OH-DPAT had anxiogenic effects when injected into the dorsal hippocampus or the lateral septum.4.4. These ligands were without effect on Trial 1 in the plus-maze when injected into the dorsal hippocampus, but had anxiogenic effects when injected into the lateral septum.5.5. On Trial 2 in the elevated plus-maze, nicotine had an anxiolytic effect, but 8-OH-DPAT had an aaxiogenic effect when injected into the dorsal hippocampus.
Anxious states are emotional states associated with an increase in avoidance behavior, particularly in situations where a conflict between approach and avoidance occurs, as when both potential rewarding outcomes and potential aversive outcomes exist. An important component of anxious states is that they are trans-situational, transferring from one situation to another. Serotonergic systems play an important role in modulating anxious states. Serotonergic signaling can either facilitate or attenuate anxious states, depending on the site of action and the specific serotonin receptor subtype involved. In this chapter, we present an operational definition of anxious states, describe a number of stimuli that can induce anxious states with distinct time-courses, and consider the evidence that serotonergic systems play a role in modulation of these anxious states. We focus on a subpopulation of serotonergic neurons that projects to forebrain limbic structures implicated in the regulation of anxious states, including the ventral hippocampus/subiculum and the basolateral amygdaloid complex. We then compare and contrast this serotonergic system with another serotonergic system implicated in the inhibition of panic-like responses, a principal component of a subset of anxiety disorders in humans.
Intra-cerebral (i.c.) microinfusion of selective receptor agonists and antagonists into behaving animals can provide both neuroanatomical and neurochemical insights into the neural mechanisms of anxiety. However, there have been no systematic reviews of the results of this experimental approach that include both a range of unconditioned anxiety reactions and a sufficiently broad theoretical context. Here we focus on amino acid, monoamine, cholinergic and peptidergic receptor ligands microinfused into neural structures previously implicated in anxiety, and subsequent behavioral effects in animal models of unconditioned anxiety or fear. GABAA receptor agonists and glutamate receptor antagonists produced the most robust anxiolytic-like behavioral effects, in the majority of neural substrates and animal models. In contrast, ligands of the other receptor systems had more selective, site-specific anti-anxiety effects. For example, 5-HT1A receptor agonists produced anxiolytic-like effects in the raphe nuclei, but inconsistent effects in the amygdala, septum, and hippocampus. Conversely, 5-HT3 receptor antagonists produced anxiolytic-like effects in the amygdala but not in the raphe nuclei. Nicotinic receptor agonists produced anxiolytic-like effects in the raphe and anxiogenic effects in the septum and hippocampus. Unexpectedly, physostigmine, a general cholinergic agonist, produced anxiolytic-like effects in the hippocampus. Neuropeptide receptors, although they are popular targets for the development of selective anxiolytic agents, had the least reliable effects across different animal models and brain structures, perhaps due in part to the fact that selective receptor ligands are relatively scarce. While some inconsistencies in the microinfusion data can easily be attributed to pharmacological variables such as dose or ligand selectivity, in other instances pharmacological explanations are more difficult to invoke: e.g., even the same dose of a known anxiolytic compound (midazolam) with a known mechanism of action (the benzodiazepine–GABAA receptor complex), can selectively affect different fear reactions depending upon the different subregions of the nucleus into which it is infused (CeA versus BLA). These particular functional dissociations are important and may depend on the ability of a GABAA receptor agonist to interact with distinct isoforms and combinations of GABAA receptor subunits (e.g., α1-6, β1-3, ϒ1-2, δ), many of which are unevenly distributed throughout the brain. Although this molecular hypothesis awaits thorough evaluation, the microinfusion data overall give some support for a model of “anxiety” that is functionally segregated along different levels of a neural hierarchy, analogous in some ways to the organization of sensorimotor systems.
The effects of chronic corticosterone treatment (100 mg pellet implanted for 1 week) were assessed in animal tests of anxiety, exploration and motor activity, and changes in binding to 5-HT1A and 5-HT2A receptors, and the 5-HT transporter, were measured. At the end of the week's treatment, the corticosterone concentration was significantly elevated and there were significant decreases in adrenal, thymus and body weights. However, there were no changes in the measures of anxiety in the social interaction test or on trials 1 and 2 of the elevated plus-maze. Also supporting a dissociation between anxiety and elevated corticosterone concentrations are previous findings that benzodiazepine withdrawal causes increased anxiety but no change in corticosteroid concentrations. Therefore these two situations provide a double dissociation between anxiety and elevated corticosteroids. Decreased 5-HT1A receptor binding in the dentate gyrus and increased 5-HT2A receptor binding in the parietal cortex was found following chronic corticosterone treatment. This reciprocal relationship between 5-HT1A and 5-HT2A receptors has been proposed to be important in mediating depression. The significant decreases in motor activity observed in all the test situations would be compatible with this proposal. Thus the constellation of behavioural and biochemical changes detected after chronic corticosterone treatment is more pertinent to depression than anxiety. One week after removal of the pellets, the behavioural and neurochernical changes had disappeared and the only differences to remain were decreased adrenal, thymus and body weights in the animals that had been treated chronically with corticosterone.
A review of the literature suggests that the dorsal hippocampal serotonergic system, and, in particular, the postsynaptic 5-HT1A receptor, mediates an anxiogenic response, whereas endogenous dorsal hippocampal cholinergic tone mediates an anxiolytic response. Accordingly, it has been shown that direct dorsal hippocampal administration of the 5-HT1A receptor agonist, 8-OH-DPAT, the nicotinic receptor antagonist, mecamylamine, and the M1 muscarinic receptor antagonist, pirenzepine, all have anxiogenic effects in rats tested in the social interaction test. It is therefore surprising that nicotine also has an anxiogenic effect in this test following dorsal hippocampal administration. However, the anxiogenic effects of mecamylamine and nicotine in the dorsal hippocampus are blocked by coadministration of the 5-HT1A receptor antagonist, WAY 100635, suggesting that both of these compounds act by enhancing hippocampal serotonergic transmission, thereby stimulating postsynaptic 5-HT1A receptors. This conclusion is supported by the observation that both nicotine and mecamylamine stimulate basal [3H]-5-HT release from dorsal hippocampal slices. A possible mechanism by which nicotinic receptor ligands modulate hippocampal 5-HT release is discussed, and it is proposed that the dorsal hippocampal serotonergic and cholinergic systems are tightly coupled and function antagonistically in the modulation of anxiety, as measured in the social interaction test. These systems are relatively unimportant in controlling behaviour on trial 1 in the plus-maze. On trial 2 in the elevated plus-maze, a model of specific phobia, the endogenous cholinergic system, nicotine, and the M1 receptor agonist, McN-A-343, all mediate an anxiolytic effect, whereas stimulation of 5-HT1A receptors mediates an anxiogenic effect. It is proposed that the hippocampus may predominantly control the avoidance components of phobic anxiety, with other regions, such as the dorsomedial hypothalamus, controlling the escape components.
The effects of escapable and yoked inescapable electric tailshocks on extracellular levels of serotonin (5-HT) in the dorsal raphe nucleus were measured by in vivo microdialysis. In comparison to either control rats or to their own preshock baseline, rats exposed to inescapable shock showed an increase in extracellular 5-HT within 25 min of shock initiation, and 5-HT levels continued to rise during the remainder of the shock session. Rats that were exposed to comparable shock treatment, but that were given the opportunity to escape, did not show an increase in 5-HT. Rats that were restrained but not shocked also did not show an increase in 5-HT. These results add further support to suggestions that serotonergic changes occur in the dorsal raphe nucleus during inescapable shock and that such changes may contribute to the behavioral effects of inescapable shock.
The effects of escapable and yoked inescapable electric tailshocks on extracellular levels of serotonin (5-HT) in the basolateral amygdala were measured by in vivo microdialysis. Inescapable, but not escapable, shock increased extracellular 5-HT in the amygdala relative to restrained controls. Basal levels of 5-HT were elevated 24 h after inescapable shock, and previously inescapably shocked subjects exhibited an exaggerated 5-HT response to two brief footshocks. Levels of extracellular 5-HIAA did not follow any particular pattern and were not correlated with the changes in 5-HT.
Dissertação (mestrado)—Universidade de Brasília, Instituto de Psicologia, Departamento de Processos Psicológicos Básicos, 2010. O presente estudo investigou os efeitos do bloqueio farmacológico dos receptores 5-HT2C do hipocampo ventral (HV) sobre os níveis de ansiedade de ratos induzidos pela injeção sistêmica de agonistas 5-HT2C. Dez minutos após injeções intraperitoneais (i.p.) com salina (0,9%) ou com o agonista 5-HT2C WAY-161503 (3mg/kg), ratos foram microinjetados bilateralmente no HV com salina ou com o antagonista seletivo de receptores 5-HT2C, SB-242084, nas doses de 0,1, 0,5 ou 1,5 ??g/0.2??l.. Cinco minutos após as microinjeções, cada animal foi exposto por cinco minutos ao Labirinto em Cruz Elevado (LCE). As seguintes categorias comportamentais foram registradas como índice de ansiedade: porcentagens de entrada e de tempo gasto nos braços abertos, tempo gasto nas categorias espreitar e esquadrinhar, bem como o número de explorações da extremidade dos braços abertos. O número absoluto de entradas nos braços fechados foi utilizado como índice de atividade locomotora. Os resultados indicaram efeitos ansiogênicos nos animais pré-tratados perifericamente com o agonista WAY-161503 e microinjetados com salina no HV. A microinjeção do antagonista 5-HT2C SB-242084 no HV bloqueou os efeitos ansiogênicos induzidos por injeções i.p. do WAY-161503. Tais resultados apontam para uma participação dos receptores 5-HT2C do HV na modulação de estados de ansiedade de ratos expostos ao LCE _________________________________________________________________________________ ABSTRACT The present study investigated the effects of pharmacological blockade of 5-HT2C receptors of the ventral hippocampus (VH) on anxiety levels of rats induced by 5-HT2C agonists. Ten minutes after intraperitoneal (i.p.) injections of either saline (0.9%) or the 5-HT2C agonist WAY-161503 (3mg/kg), rats were bilaterally microinjected in the VH with saline or with the selective 5-HT2C antagonist SB-242084 at doses of 0.1, 0.5 or 1.5 μg/0.2 μl. Five minutes after the microinjections, each animal was exposed for five minutes to the Elevated Plus-Maze (EPM). The following behavioral categories were recorded as anxiety indexes: percentages of open arm entries and of time on open- arms, time spent on risk-assessment and scanning, as well as the number of visits to the extremity of the open-arms. The absolute number of closed arm entries was used locomotor activity index. Results indicated anxiogenic effects on animals peripherically pre-treated with the agonist WAY-161503 and microinjected with saline in the VH. Microinjection of the 5-HT2C antagonist SB-242084 in the VH blocked the anxiogenic effects induced by i.p. WAY-161503 injections. These outcomes point toward participation of 5-HT2C receptors in the VH in the modulation of anxiety states in rats exposed to EPM.
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Sodium lactate (60 and 120 mg/kg), isoproterenol (0·1–0·6 mg/kg), and yohimbine (1·25-5 mg/kg) were investigated in two animal tests of anxiety (the elevated plus-maze and the social interaction test). Rats were also scored for panic-like behaviour following administration of these panic-inducing agents and following inhalation of air supplemented with CO2 (5 and 20 per cent). None of the drugs changed the time spent in social interaction or evoked panic-like behaviour. In the elevated plus-maze, sodium lactate was without effect. The highest dose of isoproterenol (0·6 mg/kg) reduced the percentage of time spent on the open arms, and yohimbine reduced both the percentage of entries made onto the open arms and the percentage of time spent on the open arms, indicating anxiogenic activity. The lack of a strong anxiogenic profile with the pro-panic compounds suggests that anxiety and panic may be biologically distinct.
A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
One of the proposed mechanisms of action for the anxiolytic effects of the benzodiazepines is via a decrease in central serotonergic neurotransmission. The aim of this study was to combine in vivo microdialysis in the rat with behaviour on the elevated X-maze to determine changes in 5-HT release in the ventral hippocampus with concomitant measurement of behaviour. Twenty minutes exposure to the elevated X-maze resulted in an increase in extracellular 5-HT in the ventral hippocampus with no change in extracellular 5-HIAA. Restricting the rat to either the open or the closed arms produced an increase in extracellular 5-HT, however the increase in 5-HT when restricted to the open arms was not significantly greater than that on the closed arms. Forty minutes pretreatment with diazepam (2.5 mg kg-1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus and had an anxiolytic profile over 5 min and 20 min exposures of the rats to the X-maze. Diazepam had no effect on basal 5-HT levels before exposure to the X-maze but reduced extracellular 5-HT levels when the animal was returned to the holding cage. Forty minutes pretreatment with the .5-HT1A receptor partial agonist ipsapirone (1 mg kg-1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus but did not produce behaviour different from vehicle controls after 5 or 20 min periods on the X-maze.(ABSTRACT TRUNCATED AT 250 WORDS)
Buspirone has been available in the United States for over four years for the treatment of anxiety. It was anticipated this drug would offer certain advantages over the established benzodiazepines. In contrast to diazepam, early studies found no evidence for the interaction of buspirone with GABAergic mechanisms. Behavioural, electrophysiological and receptor binding experiments gradually led to the idea that buspirone owes much of its anxiolytic activity to its ability to attenuate central 5-hydroxytryptamine neurotransmission. Specifically, it appears to act as an agonist at presynaptic 5-HT1A receptors, particularly in the raphe nuclei. Although buspirone also shows an affinity for dopamine D2 receptors, where it seems to behave as an antagonist, there is much doubt that this effect is related to its anxiolytic action. Even though buspirone and the benzodiazepines do not obviously share a common mode of action, the possibility is discussed that there is an underlying common mechanism of responsible for their antianxiety effects.
Chlordiazepoxide (CDP 7.5 mg/kg) had a significant anxiolytic effect in rats tested on the plus-maze for the first time. On a second trial the control scores did not change, but those of the CDP group did and they no longer differed from controls. Rats previously tested undrugged or after flumazenil (4 mg/kg) also failed to show an anxiolytic response to CDP. Thus this phenomenon of one-trial tolerance depended on prior experience with the plus-maze. It also depended on CDP acting at the benzodiazepine receptors on trial 2, since the joint administration of CDP and flumazenil on trial 2 reversed the phenomenon.
The behavioural and biochemical response to the 5-HT1-like receptor compounds, 5-carboxamidotryptamine (5-CT), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone and ipsapirone and the GABA agonist, muscimol, injected into the dorsal raphé nucleus (DRN) are reported. All compounds increased social interaction under high light, unfamiliar conditions and increased punished responding in a Vogel conflict test. At doses ranging from 5-25 times greater than those which were effective in these anxiety models, muscimol, 5-CT and 8-OH-DPAT induced a marked hypothermia and a flattening of body posture. Buspirone, on the other hand, failed to induce a significant reduction in core temperature or produce a marked flattening of posture in all animals, even at doses 100 times those effective in anxiety models. Following injection of muscimol, 5-CT, 8-OH-DPAT and buspirone into the dorsal raphé nucleus, all tended to reduce the 5-HIAA:5-HT ratios in the frontal cortex, hippocampus and hypothalamus. These findings, together with available electrophysiological data suggest that these behavioural responses are a consequence of a depression of the firing of cells in the dorsal raphé nucleus, with a corresponding decrease in functional activity of 5-HT in the forebrain.
The effect of manipulating the activity of central 5-hydroxytryptamine (5-HT) neurones on extracellular 5-HT in ventral hippocampus of the chloral hydrate-anaesthetized rat was studied using the brain perfusion method, microdialysis. Basal levels of 5-HT in the dialysates were close to the detection limits of our assay using HPLC with electrochemical detection. However, addition of the selective 5-HT reuptake inhibitor citalopram (10(-6) M) to the perfusion medium produced readily measurable amounts of dialysate 5-HT. Citalopram, therefore, was used throughout our experiments. Hippocampal dialysate levels of 5-HT sharply declined over the first hour after dialysis probe implantation, but then became constant. This stable output of 5-HT was reduced by 57% in rats treated 14 days previously with intracerebroventricular injections of the 5-HT neurotoxin 5,7-dihydroxytryptamine. Electrical stimulation (1-ms pulse width, 300 microA, 2-20 Hz) of the dorsal raphe nucleus for 20 min caused a rapid rise in hippocampal 5-HT output, which immediately declined on cessation of the stimulus and was frequency-dependent. Addition of tetrodotoxin (10(-6) M) to the perfusion medium reduced 5-HT levels to 75% of predrug values. Injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (0.5 and 2.5 micrograms) into the dorsal raphe nucleus caused a dose-related fall in hippocampal output of 5-HT compared to saline-injected controls. We conclude from these data that the spontaneous output of endogenous 5-HT into hippocampal dialysates, measured under our experimental conditions, predominantly originates from central 5-HT neurones and changes in accordance with their electrical activity.
Infusion of the serotonin-1A (5-HT1A) agonist, 8-hydroxy-2-di(n-propylamino)tetralin (8-OHDPAT) (0.5, 1.0 and 2.0 micrograms) into the dorsal raphe, decreased extracellular 5-HT as measured by dialysis in the ventral hippocampus and also decreased 5-HT synthesis in both the hippocampus and the rest of the brain as measured by 5-hydroxytryptophan (5-HTP) accumulation following decarboxylase inhibition by NSD 1015.
A two‐compartment exploratory test was used to assess the role of central 5‐hydroxytryptaminergic neurones in the anxiolytic activity of buspirone in rats.
Buspirone 0.1 mg kg ⁻¹ , administered subcutaneously 15 min before testing, significantly increased black‐white transitions (BWT) in control rats but had no effect in animals injected intra‐cerebroventricularly one week before with 150 μg 5,7‐dihydroxytryptamine (in 20 μl).
Infusion of buspirone in the median raphe (but not in the dorsal raphe) significantly enhanced BWT, at doses from 1 μg to 10 μg (in 0.5 μl). Buspirone 5 and 10 μg, but not 1 μg, administered in the median raphe, significantly enhanced motor activity of rats during the first 10 min of testing in the activity cages.
The effect on BWT of 5 μg buspirone in the median raphe was completely antagonized in animals which had received either 5,7‐dihydroxytryptamine intraventricularly, 150 μg (in 20 μl), one week before or an infusion of 0.1 μg (in 0.5 μl) (−)‐propranolol in the same area 5 min before. (−)‐Propranolol infused in the median raphe did not modify the effect of buspirone on locomotion.
Infusion of 5 μg buspirone (in 0.5 μl) in the median raphe significantly enhanced punished responses in a conflict test with no effect on unpunished responding. Buspirone infused in the dorsal raphe had no effect on punished or unpunished responding over a wide dose range.
The results indicate that at the relatively low dose used in the present study buspirone produces an anxiolytic effect by acting on central 5‐hydroxytryptaminergic neurones. It is likely that activation of 5‐hydroxytryptamine 1A ‐receptors in the median raphe is involved.
The effects of a selective serotonin 1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), were studied in two animal models of anxiety. Peripherally injected 8-OH-DPAT in doses ranging from 0.125 to 2.0 mg/kg did not increase black-white transitions (BWT) and black square entries (BSE) in a two-compartment exploratory test or punished responding in a test of conditioned suppression of drinking. With 2.0 mg/kg 8-OH-DPAT BSE and unpunished responding were reduced. In an investigation of the drinking time of water-deprived rats, naive or habituated to the test environment, 1.0 and 2.0 mg/kg 8-OH-DPAT increased the drinking time of naive rats but 2.0 mg/kg 8-OH-DPAT reduced that of habituated animals. In animals deprived of water for 48 h or subjected to immobilization stress for 2 h, 1.0 mg/kg 8-OH-DPAT increased BWT and BSE values in the two-compartment exploratory test. Infusions of 5 micrograms/0.5 microliter 8-OH-DPAT in the nucleus raphe medianus increased BWT and BSE values in the exploratory test and punished responding in the test of conditioned suppression of drinking, whereas the same dose of 8-OH-DPAT injected in the nucleus raphe dorsalis had no effect on punished but suppressed unpunished responding. The effects of 8-OH-DPAT are only detectable in the appropriate experimental conditions. When injected systemically, the effects are evident when a state of arousal of the animals contributes to the overall behavioural output. 8-OH-DPAT shows effects comparable to those of established anxiolytics such as benzodiazepines and barbiturates when it is injected in the nucleus raphe medianus, but not in the dorsalis.(ABSTRACT TRUNCATED AT 250 WORDS)
A direct comparison was made of the effects of serotonin 5-HT1A and 5-HT1B selective compounds on the spontaneous firing rate of dorsal raphe serotoninergic neurons in chloral-hydrate-anesthetized rats. Following intravenous administration, the 5-HT1A selective compounds ipsapirone (TVX Q 7821) and LY 165163 potently inhibited single-unit activity in a dose-dependent manner whereas the 5-HT1B selective compounds, m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFMPP), displayed only weak or irregular actions. Low microiontophoretic currents of ipsapirone and LY 165163 were also effective in suppressing spontaneous firing; dose-response relationships for the 5-HT1A compounds were indistinguishable from that of 5-HT itself. In contrast, dorsal raphe neurons were only weakly responsive to microiontophoretic application of mCPP and TFMPP; dose-response relationships for the 5-HT1B compounds were significantly displaced from that of 5-HT. In intracellular studies, ipsapirone and LY 165163, when added to the media bathing brain slices, mimicked the actions of 5-HT in hyperpolarizing dorsal raphe cell membranes and decreasing input resistance; however, the maximal effects of the 5-HT1A compounds on these membrane properties exceeded those of 5-HT. In summary, dorsal raphe 5-HT neurons appear highly responsive to 5-HT1A, but not to 5-HT1B compounds; these findings are discussed with regard to the 5-HT receptor subtypes as candidates for the somatodendritic autoreceptor of dorsal raphe neurons.
This study analyses at which site, pre- or postsynaptic, the 5-HT1A ligands--8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ipsapirone--induce their anxiolytic action. The experimental anxiety was assessed in the social interaction test. An anxiolytic action was observed after the systemic administration of 8-OH-DPAT (0.25 and 0.5 mg/kg) and ipsapirone (5 but not 10 mg/kg). In 5,7-dihydroxytryptamine (5,7-DHT, 150 micrograms/10 microliters) lesioned rats the anxiolytic effect of 8-OH-DPAT and ipsapirone was not observed, suggesting a presynaptic action of these drugs. When directly injected into the dorsal raphe nucleus 8-OH-DPAT (0.1 microgram/microliter) and ipsapirone (0.2 microgram/microliter), both compounds produce anxiolytic effects. At same doses, these drugs lacked an effect after their intrahippocampal infusion. All data strongly suggest that both drugs act presynaptically to reduce the anxiety levels in the social interaction paradigm.
An overview of the behavioral data arising from the vast literature concerning the involvement of 5-hydroxytryptamine (5-HT) neurotransmission in the regulation of anxiety is presented. More than 1300 experiments were carried out in this area and they provide evidence that: (1) results obtained in ethologically based animal models of anxiety with drugs stimulating 5-HT transmission are most consistent with the classic 5-HT hypothesis of anxiety in that they show an increase in animals' emotional reactivity; (2) no category of anti-anxiety models are selectively sensitive to the anxiolytic-like effects of drugs targetting 5-HT1A, 5-HT2A or 5-HT2C receptor subtypes; (3) anxiolytic-like effects of 5-HT3 receptor antagonists, in the great part, are revealed by models based on spontaneous behaviors. Taken together, these observations lead to the conclusion that different 5-HT mechanisms, mediated by different receptor subtypes, are involved in the genesis of anxiety.
The potential 5-HT1A antagonist properties of the beta-antagonist tertatolol were assessed using biochemical and electrophysiological assays in the rat. (+/-) Tertatolol bound with high affinity (Ki = 38 nM) to 5-HT1A sites labelled by [3H]8-OH-DPAT in hippocampal membranes. The (-)stereoisomer (Ki = 18 nM) was about 50-fold more potent than the (+)stereoisomer (Ki = 864 nM) to inhibit the specific binding of [3H]-8-OH-DPAT. As expected of a 5-HT1A antagonist, (-)tertatolol prevented in a concentration-dependent manner (Ki = 24 nM) the inhibitory effect of 8-OH-DPAT on forskolin-stimulated adenylate cyclase activity in rat hippocampal homogenates. Furthermore in vivo pretreatment with (-)tertatolol (5 mg/kg s.c.) significantly reduced the inhibitory influence of 8-OH-DPAT (0.3 mg/kg s.c.) on the accumulation of 5-hydroxytryptophan in various brain areas after the blockade of aromatic L-amino acid decarboxylase by NSD-1015 (100 mg/kg i.p.). In vitro (in brainstem slices; Ki approximately 50 nM) and in vivo (in chloral hydrate anaesthetized rats; ID50 approximately 0.40 mg/kg i.v.), (-)tertatolol prevented the inhibitory effects of the 5-HT1A receptor agonists 8-OH-DPAT, ipsapirone and lesopitron on the firing rate of serotoninergic neurones within the dorsal raphe nucleus. In about 25% of these neurones, the basal firing rate was significantly increased by (-)tertatolol (up to +47% in vitro, and +30% in vivo). These data indicate that (-)tertatolol is a potent competitive antagonist at both pre (in the dorsal raphe nucleus)-and post (in the hippocampus)-synaptic 5-HT1A receptors in the rat brain.
The effects of (S)-WAY 100135 ((S)-N-tert-butyl-3-(4-(2-methoxyphenyl)- piperazin-1-yl)-2-phenyl-propanamide dihydrochloride; 2.5-20.0 mg/kg), a 5-HT1A receptor antagonist, on the behaviour of male mice were examined in the elevated plus-maze test of anxiety. An ethological scoring technique was used to provide a comprehensive profile of drug action. Only minor changes in behaviour were observed at 2.5 and 5.0 mg/kg, and consisted of reductions in some (though not all) risk assessment measures. At 10 mg/kg, the compound increased percent open arm entries and percent open arm time, without altering general activity levels. This classic anxiolytic-like profile was confirmed by major reductions in risk assessment measures including protected head-dips and protected stretched attend postures. Although many of the same changes were also observed at 20 mg/kg, the absence of an effect on percent open arm time and a tendency towards increased non-exploratory behaviour suggested (1) some loss of anxiolytic activity and (2) a possible contribution of non-specific factors at higher doses. Present findings indicate that (S)-WAY 100135 produces clear anxiolytic-like effects in the murine elevated plus-maze, a profile that can be distinguished from that produced by 5-HT1A receptor partial agonists in the same test.
A factor analysis of the scores from rats given two trials in the elevated plus-maze showed that four independent factors emerged. Measures of anxiolytic activity on trial 1 (number of open arm entries and time spent on open arms) loaded on factor 1, measures of anxiolytic activity on trial 2 loaded on factor 2, the measure of general activity (number of closed arm entries) on both trials loaded on factor 3, and a measure of decision time (time spent in central square) for both trials loaded on factor 4. The independence of trials 1 and 2 anxiety measures raises the possibility that the state of anxiety/fear on the second trial in the plus-maze is qualitatively different from that on trial 1. This difference is reflected in the loss of anxiolytic action of diazepam (2 mg/kg) on trial 2. However, this occurs only when the trials are short (5 min); when they are longer (10 min) diazepam retains anxiolytic efficacy. It is concluded that during a brief (5 min) trial in the plus-maze rats acquire a specific phobic anxiety, which is relatively resistant to benzodiazepines. With a longer exposure to the plus-maze this form of fear extinguishes.
In rats, the 5-HT1A receptor full agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the 5-HT1A receptor partial agonists ipsapirone and buspirone dose dependently and completely inhibited shock-induced ultrasonic vocalization after systemic injection and after microinjection into the dorsal raphe nucleus, a brain region rich in somatodendritic 5-HT1A receptors. As compared with injection into the dorsal raphe nucleus, ipsapirone and 8-OH-DPAT were significantly less potent after microinjection into the lateral ventricle or the median raphe nucleus. Depletion of brain 5-HT (5-hydroxytryptamine) by means of 5,7-dihydroxytryptamine or parachlorophenylalanine inhibited ultrasonic vocalization. In lesioned rats, however, ipsapirone (i.p. or dorsal raphe nucleus) and 8-OH-DPAT (dorsal raphe nucleus) retained their ability to inhibit ultrasonic vocalization and, in non-lesioned rats, bilateral injection of ipsapirone, buspirone and 8-OH-DPAT into the dorsal hippocampus and the amygdala - two brain regions rich in postsynaptic 5-HT1A receptors - also inhibited ultrasonic vocalization. In a Geller-Seifter conflict test, i.p. and local injection of 8-OH-DPAT in the dorsal raphe nucleus and the hippocampus selectively enhanced punished responding. It is suggested that both presynaptic and (possibly to a lesser extent) postsynaptic 5-HT1A receptors are involved in the anxiolytic effects of ipsapirone, buspirone, and 8-OH-DPAT.
Administration of the 5-HT1A receptor agonist (+-)-8-Hydroxy-dipropylaminotetralin (8-OH DPAT, 50 ng) into the dorsal raphé nucleus (DRN) increased social interaction but did not change the motor activity of rats tested in high light, thus indicating an anxiolytic response. This effect was blocked by coadministration of the 5-HT1A antagonist, tertatolol (3 micrograms). In contrast, 8-OH DPAT (50 and 100 ng) was without effect on social interaction when administered to the DRN projection area in the ventral hippocampus, but did change locomotor activity. The effects depended on the light level and dose: thus when the rats were tested in low light, 50 ng increased locomotor activity, but in high light a decrease was found with 100 ng and also an induction of wet dog-shakes. Thus, our results support the importance of the somatodendritic autoreceptors in the DRN in alleviating anxiety, whereas the post-synaptic receptors in the ventral hippocampus play no role. They do, however, mediate changes in activity and the 5-HT syndrome.
Responses to serotonergic drugs in animal models of 'anxiety' are reviewed with emphasis on the elevated X-maze. Evidence for the 'classic' hypothesis, that decreasing serotonergic function is anxiolytic and increasing it anxiogenic, is most consistent in models of behavioural inhibition where the stimulus inhibits an approach response (conflict models). However, paradoxical drug effects are also frequent, especially where the aversive stimulus evokes an active response. Both types of drug effect are equally frequent in the elevated X-maze. 'Anxiety' models may detect multiple sites and mechanisms of action of the same drug; this may indicate multiple anxiety-related neurological mechanisms in the brain. However, not all drug effects in 'anxiety' models are necessarily related to anxiety itself. It is possible that cognitive factors may affect stimulus evaluation, and response inhibition by an aversive stimulus may be a special case of a wider role for serotonin in behavioural control. Clinical implications of these observations are considered.
In naive rats benzodiazepines have clear anxiolytic effects in the elevated plus-maze, but in rats with previous plus-maze experience benzodiazepines are ineffective. This phenomenon does not depend on the drug state on trial 1 or on the inter-trial interval and generalises across mazes of different material; it is dependent on experience of the open arm. The phenomenon of "one-trial tolerance" to the anxiolytic effect of benzodiazepines is not seen in other animal tests; and there is no equivalent phenomenon of "one-trial withdrawal" or of tolerance to anxiogenic effects in the plus-maze. The phenomenon is not seen in unhandled rats, in rats given longer trials in the plus-maze, or in those given an amnesic treatment on trial 1. It is suggested that during the first 5 min in the elevated plus-maze the rats are acquiring a fear of heights and it is this phobic anxiety state that is measured during the second 5-min trial. Thus the nature of the anxiety generated by the maze is different on trials 1 and 2. The results of a factor analysis study confirm this conclusion.
The interaction of tertatolol (d,l-hydroxy-2'-t-butylamino-3'propyloxy-8-thiochromane HCl) with 5-hydroxytryptamine (serotonin; 5-HT) receptors in several brain areas were investigated. Both ligand binding techniques and an electrophysiological approach were used. First, the affinity of tertatolol for different 5-HT receptor subtypes was measured, as assayed by a competition binding experiment using specific ligands in several brain areas. It was found that (-)-tertatolol binds to 5-HT1 receptor subtypes in rat brain, particularly the 5-HT1A subtype in the hippocampus (Ki = 5.9 nM). (-)-Tertatolol showed much lower affinity for 5-HT1B (Ki = 118.4 nM), 5-HT1C (Ki = 699.6 nM) and 5-HT2 (Ki = 678.6 nM) receptors. The binding of tertatolol to hippocampal 5-HT1A receptors was stereospecific in that the affinity of (+)-tertatolol to these receptors (Ki = 311.6 nM) was about 20 times lower as compared to that of (-)-tertatolol. There was no significant binding of tertatolol to 5-HT1D, 5-HT3, alpha-1 adrenergic receptors or to the serotonin uptake site. Electrophysiological techniques were used to study the effects of (-)-tertatolol on the activity of 5-HT-containing neurons in the rat dorsal raphe nucleus. Acute i.v. injection of (-)-tertatolol caused a slight increase in the basal firing rate of the majority of 5-HT neurons studied. Pretreatment with (-)-tertatolol (1 mg/kg i.v.) significantly reduced the inhibitory effect of 8-hydroxy-2-(di-n-proylamino) tetralin (0.25-64 micrograms/kg i.v.) on the firing rate of dorsal raphe nucleus 5-HT neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
The biological basis of anxiety
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