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Author (up) Bencan, Z.; Sledge, D.; Levin, E.D. file  url
openurl 
  Title Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety Type Journal Article
  Year 2009 Publication Pharmacology, Biochemistry, and Behavior Abbreviated Journal Pharmacol Biochem Behav  
  Volume 94 Issue 1 Pages 75-80  
  Keywords Animals; Anti-Anxiety Agents/*therapeutic use; Anxiety/*drug therapy; Behavior, Animal/drug effects; Benzodiazepines/administration & dosage/therapeutic use; Buspirone/administration & dosage/*therapeutic use; Chlordiazepoxide/administration & dosage/*therapeutic use; Cholinergic Agents/administration & dosage/therapeutic use; Diazepam/administration & dosage/*therapeutic use; *Disease Models, Animal; Diving; Dose-Response Relationship, Drug; Exploratory Behavior/drug effects; Imaging, Three-Dimensional/methods; Serotonin Agents/administration & dosage/therapeutic use; Stress, Psychological; Time Factors; *Zebrafish  
  Abstract Zebrafish are becoming more widely used to study neurobehavioral pharmacology. We have developed a method to assess novel environment diving behavior of zebrafish as a model of stress response and anxiolytic drug effects. In a novel tank, zebrafish dwell in the bottom of the tank initially and then increase their swimming exploration to higher levels over time. We previously found that nicotine, which has anxiolytic effects in rodents and humans, significantly lessens the novel tank diving response in zebrafish. The specificity of the diving effect was validated with a novel vs. non-novel test tank. The novel tank diving response of zebrafish was tested when given three anxiolytic drugs from two different chemical and pharmacological classes: buspirone, chlordiazepoxide and diazepam. When the test tank was novel the diving response was clearly seen whereas it was significantly reduced when the test tank was not novel. Buspirone, a serotonergic (5HT(1A) receptor agonist) anxiolytic drug with some D(2) dopaminergic effect, had a pronounced anxiolytic-like effect in the zebrafish diving model at doses that did not have sedative effects. In contrast, chlordiazepoxide, a benzodiazepine anxiolytic drug, which is an effective agonist at GABA-A receptors, did not produce signs of anxiolysis in zebrafish over a broad dose range up to those that caused sedation. Diazepam another benzodiazepine anxiolytic drug did produce an anxiolytic effect at doses that did not cause sedation. The zebrafish novel tank diving task can be useful in discriminating anxiolytic drugs of several classes (serotonergic, benzodiazepines and nicotinic).  
  Call Number Serial 209  
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Author (up) Briggs, C.A.; Gronlien, J.H.; Curzon, P.; Timmermann, D.B.; Ween, H.; Thorin-Hagene, K.; Kerr, P.; Anderson, D.J.; Malysz, J.; Dyhring, T.; Olsen, G.M.; Peters, D.; Bunnelle, W.H.; Gopalakrishnan, M. file  url
openurl 
  Title Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors Type Journal Article
  Year 2009 Publication British Journal of Pharmacology Abbreviated Journal Br J Pharmacol  
  Volume 158 Issue 6 Pages 1486-1494  
  Keywords Allosteric Regulation; Animals; Avoidance Learning/drug effects; Azabicyclo Compounds/administration & dosage/*pharmacology; Behavior, Animal/drug effects; Cell Line; Cognition Disorders/drug therapy/physiopathology; Dose-Response Relationship, Drug; Furans/administration & dosage/*pharmacology; Humans; Male; Mice; Nicotinic Agonists/*pharmacology; Oocytes/drug effects/metabolism; Oxadiazoles/administration & dosage/*pharmacology; Pyridazines/pharmacology; Pyrroles/pharmacology; Rats; Receptors, Nicotinic/*drug effects/metabolism; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract BACKGROUND AND PURPOSE: Several agonists of the alpha7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid alpha7 nAChR desensitization in vitro; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved. EXPERIMENTAL APPROACH: Two structurally related alpha7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm. KEY RESULTS: NS6784 activated human and rat alpha7 nAChR with EC(50)s of 0.72 and 0.88 microM, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at alpha7 nAChR (<2% in oocytes, < or =8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of alpha7 nAChRs or using the slowly desensitizing alpha7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A-582941. In contrast, NS6740 did not enhance performance, but blocked effects of A-582941. CONCLUSIONS AND IMPLICATIONS: Collectively, these findings suggest that a degree of alpha7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to alpha7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of alpha7 nAChR antagonists with favourable CNS penetration.  
  Call Number Serial 1881  
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Author (up) Conrad, K.L.; Louderback, K.M.; Gessner, C.P.; Winder, D.G. file  url
doi  openurl
  Title Stress-induced alterations in anxiety-like behavior and adaptations in plasticity in the bed nucleus of the stria terminalis Type Journal Article
  Year 2011 Publication Physiology & Behavior Abbreviated Journal Physiol Behav  
  Volume 104 Issue 2 Pages 248-256  
  Keywords Adaptation, Physiological/drug effects/*physiology; Analysis of Variance; Animals; Anxiety/*etiology/*pathology; Behavior, Animal/drug effects; Biophysics; Corticosterone/adverse effects; Disease Models, Animal; Electric Stimulation; Exploratory Behavior/drug effects/physiology; Long-Term Potentiation/drug effects/*physiology; Male; Maze Learning/drug effects; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques/methods; Septal Nuclei/drug effects/*physiopathology; Social Isolation/psychology; Time Factors  
  Abstract In vulnerable individuals, exposure to stressors can result in chronic disorders such as generalized anxiety disorder (GAD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). The extended amygdala is critically implicated in mediating acute and chronic stress responsivity and anxiety-like behaviors. The bed nucleus of the stria terminalis (BNST), a subregion of the extended amygdala, serves as a relay of corticolimbic information to the paraventricular nucleus of the hypothalamus (PVN) to directly influence the stress response. To investigate the influence of the corticosteroid milieu and housing conditions on BNST function, adult C57Bl/6J were either acutely or chronically administered corticosterone (CORT, 25mg/kg in sesame oil) or vehicle (sesame oil) or were group housed or socially isolated for 1 day (acute) or 6-8 weeks (chronic). To ascertain whether these stressors could influence anxiety-like behavior, studies were performed using the novel open-field (NOF) and the elevated zero maze (EZM) tests. To investigate potential associated changes in plasticity, alterations in BNST function were assessed using ex vivo extracellular field potential recordings in the (dorsal-lateral) dlBNST and a high frequency stimulus protocol to induce long-term potentiation (LTP). Our results suggest that chronic CORT injections and chronic social isolation housing conditions lead to an increase in anxiety-like behavior on the EZM and NOF. Chronically stressed mice also displayed a parallel blunting of LTP in the dlBNST. Conversely, acute social isolation housing had no effect on anxiety-like behavior but still resulted in a blunting of LTP in the dlBNST. Collectively, our results suggest acute and chronic stressors can have a distinct profile on plasticity in the BNST that is not uniformly associated with an increase in anxiety-like behavior.  
  Call Number Serial 85  
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Author (up) File, S.E.; Seth, P. file  url
openurl 
  Title A review of 25 years of the social interaction test Type Journal Article
  Year 2003 Publication European Journal of Pharmacology Abbreviated Journal Eur J Pharmacol  
  Volume 463 Issue 1-3 Pages 35-53  
  Keywords Animals; Anti-Anxiety Agents/pharmacology; Anxiety/chemically induced/metabolism/*psychology; Behavior, Animal/drug effects; Brain/physiopathology; *Disease Models, Animal; Environment; Neuropeptides/metabolism/pharmacology; Neurotransmitter Agents/*metabolism/pharmacology; *Social Behavior; Substance Withdrawal Syndrome/etiology/psychology  
  Abstract The social interaction test of anxiety was developed 25 years ago to provide an ethologically based test that was sensitive to both anxiolytic and anxiogenic effects. It is sensitive to a number of environmental and physiological factors that can affect anxiety. It has detected anxiogenic effects of peptides such as corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and anxiolytic effects of neuropeptide Y and substance P receptor antagonists. It has successfully identified neuropharmacological sites of action of anxiogenic compounds and drug withdrawal. Effects of compounds acting on the gamma-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) systems have been extensively investigated after both systemic administration and microinjection into specific brain regions. The use of this test has, thus, played a crucial role in unravelling the neural basis of anxiety. It is hoped that in the next 25 years, the test will play a crucial role in determining the genetic basis of anxiety disorders.  
  Call Number Serial 1187  
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Author (up) Guilloux, J.-P.; David, D.J.P.; Xia, L.; Nguyen, H.T.; Rainer, Q.; Guiard, B.P.; Reperant, C.; Deltheil, T.; Toth, M.; Hen, R.; Gardier, A.M. file  url
doi  openurl
  Title Characterization of 5-HT(1A/1B)-/- mice: an animal model sensitive to anxiolytic treatments Type Journal Article
  Year 2011 Publication Neuropharmacology Abbreviated Journal Neuropharmacology  
  Volume 61 Issue 3 Pages 478-488  
  Keywords Animals; Anti-Anxiety Agents/*therapeutic use; Anxiety/*drug therapy/metabolism/physiopathology; Behavior, Animal/drug effects; Body Temperature Regulation; *Disease Models, Animal; Frontal Lobe/drug effects/metabolism; Gene Expression; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons/drug effects/metabolism; Paroxetine/therapeutic use; RNA, Messenger/metabolism; Raphe Nuclei/drug effects/metabolism; Receptor, Serotonin, 5-HT1A/genetics/*physiology; Receptor, Serotonin, 5-HT1B/genetics/*physiology; Serotonin/metabolism; Serotonin Plasma Membrane Transport Proteins/genetics/metabolism; Serotonin Uptake Inhibitors/therapeutic use; Synaptic Transmission/drug effects  
  Abstract Selective serotonin (5-HT) re-uptake inhibitors (SSRIs) are commonly used in the treatment of generalized anxiety disorder in Humans. However, because only few animal models display overt anxious-like behavior, detailed preclinical studies of the anxiolytic properties of antidepressants are still lacking. Here, we studied the neurochemical and behavioral effects of a double 5-HT(1A/1B) receptor knockout in mice (5-HT(1A/1B)-/-) as compared to their wild-type littermates (5-HT(1A/1B)+/+). It is known that single deletion of either 5-HT(1A) or 5-HT(1B) receptor induces behavioral changes that are not correlated with differences in brain serotonergic tone. Deletion of both receptors resulted in (i) higher emotionality of animals, as observed in three unconditioned paradigms of anxiety (open field, elevated plus maze and novelty suppressed feeding tests); (ii) a approximately 200% increase in the mean spontaneous firing rate of 5-HT neurons in the dorsal raphe nucleus (DRN) compared to 5-HT(1A/1B)+/+ mice; (iii) elevated basal dialysate levels of 5-HT in the DRN and frontal cortex; (iv) an exaggerated response to acute paroxetine administration in microdialysis experiments, and (v) increased basal core body temperature. These findings suggest that the deletion of both autoreceptors induces a strong anxious-like behavioral state associated with increased 5-HT neurotransmission. Interestingly, 5-HT(1A/1B)-/- mice are still sensitive to the acute administration of diazepam. Moreover, while deletion of both receptors impacted on the response to acute SSRI treatment in the forced swim test, anxiolytic-like effects of a chronic SSRI treatment were still observed in 5-HT(1A/1B)-/- mice. Thus, the 5-HT(1A/1B)-/- mouse model could be of great interest to unveil the mechanisms of action of the anxiolytic effects of SSRIs.  
  Call Number ] Serial 173  
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