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Sandra E. File - One of the best experts on this subject based on the ideXlab platform.
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Animal Tests of Anxiety
Current Protocols in Neuroscience, 2004Co-Authors: Sandra E. File, Bernard Beer, Arnold S. Lippa, Morgen T. LippaAbstract:Animal Tests of anxiety are used to screen novel compounds for anxiolytic or anxiogenic activity, to investigate the neurobiology of anxiety, and to assess the impact of other occurrences such as exposure to predator odors or early rearing experiences. This unit presents protocols for the most commonly used animal Tests of anxiety. The Geller-Seifter conflict Test, the Social Interaction Test, light/dark exploration, the elevated plus-maze, defensive burying, and the thirsty rat conflict. The protocols are described in terms of drug screening Tests, but can be modified easily for other purposes.
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Unconditioned and conditioned anxiogenic effects of the cannabinoid receptor agonist CP 55,940 in the Social Interaction Test.
Pharmacology biochemistry and behavior, 2004Co-Authors: Rachel F. Genn, Sonia Tucci, Eva María Marco, M Paz Viveros, Sandra E. FileAbstract:In spite of the addictive properties of cannabinoids, under certain circumstances, they can evoke strong anxiogenic and aversive responses in humans and in animal Tests of anxiety. Effects of different doses of CP 55,940 (10, 20, and 40 μg/kg) were Tested in the low-light, familiar (LF) apparatus Test condition of the Social Interaction Test. The 40-μg/kg dose of CP 55,940 significantly decreased the time spent in Social Interaction, indicating an anxiogenic effect. This dose also had an independent effect of reducing locomotor activity. In rats Tested undrugged 24 h after Testing with 40 μg/kg, there was a significant anxiogenic effect, indicating conditioned anxiety. The group of rats injected with 40 μg/kg immediately after the Social Interaction Test showed an unexpected significant anxiolytic effect when Tested undrugged 24 h later. In an additional experiment, rats were Tested in the high-light, familiar (HF) apparatus Test condition after 10 or 40 μg/kg, and only those that were Tested after 40 μg/kg showed an anxiogenic effect on the Test day and a conditioned anxiogenic effect when Tested undrugged 24 h later. Once again, those injected with 40 μg/kg after the Social Interaction Test displayed an anxiolytic effect when Tested undrugged 24 h later. We provide the first evidence for unconditioned and conditioned anxiogenic-like responses to a cannabinoid agonist in the Social Interaction Test.
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A review of 25 years of the Social Interaction Test.
European journal of pharmacology, 2003Co-Authors: Sandra E. File, Pallab SethAbstract: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.
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Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the Social Interaction Test in gerbils
Brain research, 2001Co-Authors: Survjit Cheeta, Sonia Tucci, Nadia M. J. Rupniak, J Sandhu, A.r Williams, Sandra E. FileAbstract:The gerbil Social Interaction Test has previously detected anxiolytic effects of nicotine and diazepam. In the present study, the high affinity substance P (NK1) receptor antagonist L-760735 (3 mg/kg) significantly increased the time spent in Social Interaction, whereas its low affinity analogue L-781773 (3 mg/kg) was without effect. Diazepam (0.1 mg/kg) and the 5-HT1A receptor agonist 8-OH-DPAT (0.003 and 0.01 mg/kg) also increased Social Interaction, whereas an acute dose of the selective serotonin re-uptake inhibitor fluoxetine (10 mg/kg) decreased the time spent in Social Interaction. Diazepam (0.1 mg/kg) significantly increased locomotor activity, but this effect was independent of the increase in Social Interaction. The other drugs Tested were without effect on locomotor activity. The present findings suggest that the gerbil Social Interaction may well provide a useful assay for detecting both anxiolytic and anxiogenic compounds, and suggests that the high affinity NK1 receptor antagonist L-760735 may prove to be useful as an anxiolytic therapy.
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Social isolation modifies nicotine s effects in animal Tests of anxiety
British Journal of Pharmacology, 2001Co-Authors: Survjit Cheeta, Elaine E. Irvine, Sandra E. FileAbstract:These experiments determined whether the housing conditions of rats influenced the effects of nicotine in two animal Tests of anxiety, Social Interaction and elevated plus-maze Tests. In animals housed singly for 7 days, (−)nicotine (0.025 mg kg−1 s.c.) was ineffective, but 0.05, 0.1 and 0.25 mg kg−1 (s.c.) significantly increased the time spent in Social Interaction, without changing locomotor activity, thus indicating anxiolytic actions. (−)Nicotine (0.45 mg kg−1 s.c.) significantly reduced Social Interaction, indicating an anxiogenic effect. However, in group-housed animals, (−)nicotine (0.025 mg kg−1 s.c.) had a significant anxiolytic effect in the Social Interaction Test, but 0.01, 0.05, 0.1, 0.25 and 0.45 mg kg−1 were ineffective. (−)Nicotine (1 mg kg−1) reduced motor activity and Social Interaction in the group-housed animals. In the elevated plus-maze, the time-course and the dose-response curve to nicotine were investigated. In both singly- and group-housed rats, (−) nicotine (0.1 – 0.45 mg kg−1 s.c.) decreased the per cent entries into, and per cent time spent on, the open arms, indicating anxiogenic effects. The housing condition influenced the time course, with significant effects at 5 and 30 min after injection in group-housed rats, and significant effects at 30 and 60 min in singly-housed rats. In the Social Interaction Test there was no difference in the scores of the first and last rats removed from group cages, whereas the order of removal from the cages did affect the scores in the elevated plus-maze. These results provide further evidence that the two animal Tests model distinct states of anxiety, and show how Social isolation powerfully modifies both anxiolytic and anxiogenic effects of nicotine. British Journal of Pharmacology (2001) 132, 1389–1395; doi:10.1038/sj.bjp.0703991
Nick Andrews - One of the best experts on this subject based on the ideXlab platform.
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evidence that the median raphe nucleus dorsal hippocampal pathway mediates diazepam withdrawal induced anxiety
Psychopharmacology, 1997Co-Authors: Nick Andrews, Luis E. Gonzalez, Cathy Fernandes, Sandra E. File, Nicholas M. BarnesAbstract:On the basis of our previous series of experiments we had postulated that the increased anxiety that occurred during diazepam withdrawal was mediated by increased 5-HT release in the hippocampus. The present series of experiments provide evidence for a major role of the median raphe nucleus (MRN) dorsal hippocampal pathway. Rats were treated once daily for 21 days with diazepam (2 mg/kg IP) and then Tested after 24 h withdrawal in the Social Interaction Test of anxiety. Relative to chronically vehicle treated animals, those withdrawn from diazepam were significantly more anxious and had significantly greater K+-evoked release of [3H]-5-hydroxytryptamine (5-HT) from slices of dorsal and of ventral regions of the hippocampus. Estimation of extracellular concentrations of 5-HT within the dorsal hippocampus, using in-vivo microdialysis, showed doubling in the levels of 5-HT in the rats withdrawn from chronic diazepam treatment. This just failed to reach significance, but 33% of the rats showed dramatic increases (650%). It was not possible to Test these animals in the Social Interaction Test, but it is proposed that only the diazepam-withdrawn rats with raised extracellular levels of 5-HT would have displayed increased anxiety. 5-HT1A receptor agonists injected into the MRN decrease the MRN firing rate, and hence the release of 5-HT in the dorsal hippocampus. As a further Test of our hypothesis, we examined the effects of MRN injection of the 5-HT1A receptor agonist, 8-OH DPAT, on animals withdrawn from diazepam and Tested in the low light familiar condition of the Social Interaction Test. 8-OH DPAT (50–200 ng) dose-dependently reversed the anxiogenic effect of diazepam withdrawal, while having no effects in chronic vehicle-treated animals. These results provide clear evidence that the MRN-dorsal hippocampal 5-HT pathway is at least one of the pathways playing an important role in mediating diazepam withdrawal-induced anxiety.
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5 ht1a and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the Social Interaction Test but not in the elevated plus maze
Brain Research, 1996Co-Authors: Luis E. Gonzalez, Nick Andrews, Sandra E. FileAbstract:In order to investigate the role of the 5-HT1A receptors of the amygdala in modulating anxiety, rats were implanted with bilateral cannulae aimed at the basolateral nucleus of the amygdala complex and infused with either artificial cerebrospinal fluid (aCSF) or the selective 5-HT1A receptor agonist 8-OH-DPAT (50-200 ng) and Tested in two animal models of anxiety. In the elevated plus-maze Test, no significant effects were detected in this dose range. In contrast, 8-OH-DPAT caused an overall reduction in levels of Social investigation, thus indicating anxiogenic actions in the Social Interaction Test. At 50 ng, 8-OH-DPAT had a selective action on anxiety, while at 200 ng there was a concomitant reduction in locomotor activity and, in some animals, signs of the 5-HT1A syndrome. Evidence that the anxiogenic effect of 8-OH-DPAT (50 ng) was due to activation of 5-HT1A receptors came from the finding that (-)-tertatolol, a 5-HT1A receptor antagonist, reversed this effect at a dose (1.5 micrograms) which was silent when given alone. The benzodiazepine receptor agonist, midazolam (1 and 2 micrograms) was bilaterally administered into the basolateral nucleus of the amygdala and evoked clear-cut anxiolytic effects in the Social Interaction Test. These data indicate that the agonist activation of post-synaptic 5-HT1A receptors in the basolateral nucleus of the amygdala may produce anxiogenic effects, while agonist activation of BDZ receptors in the same areas evokes anxiolytic effects. Our results from the Social Interaction Test are similar to those previously reported from Tests of anxiety using punished paradigms, but contrast with those found in the elevated plus-maze. Thus, it is concluded that either the two Tests have different sensitivities to midazolam and 8-OH-DPAT or more intriguingly, the Tests are evoking fundamentally different states of anxiety, with that evoked by the plus-maze being mediated via brain areas or receptors different from those studied here.
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5 ht1a receptors in the median raphe nucleus and dorsal hippocampus may mediate anxiolytic and anxiogenic behaviours respectively
European Journal of Pharmacology, 1994Co-Authors: Nick Andrews, Luis E. Gonzalez, Sandy Hogg, Sandra E. FileAbstract:The behavioural response of rats in the high light unfamiliar condition of the Social Interaction 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 μg) into the median raphe nucleus or dorsal hippocampus. In the median raphe nucleus, 8-OH-DPAT (200 ng) significantly increased Social Interaction without changing locomotor activity; lower doses were inactive. In the dorsal hippocampus, bilateral injection of 8-OH-DPAT (100 ng) significantly decreased Social Interaction, without effect on locomotor activity; both 50 and 100 ng significantly changed grooming. Tertatolol had no effect on Social Interaction following administration to the median raphe nucleus, but significantly increased locomotor activity. Bilateral injection of tertatolol into the dorsal hippocampus decreased Social Interaction and changed grooming. These effects are similar to those of 8-OH-DPAT suggesting tertatolol may have 5-HT1A receptor agonist properties. In conclusion, the findings of this study demonstrate that 5-HT1A somatodendritic autoreceptors and post-synaptic receptors mediate anxiolytic and anxiogenic effects, respectively, in the Social Interaction Test.
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diazepam withdrawal responses measured in the Social Interaction Test of anxiety and their reversal by baclofen
Psychopharmacology, 1991Co-Authors: Sandra E. File, P S Mabbutt, Nick AndrewsAbstract:After 21 days of treatment with diazepam (0.5 or 2 mg/kg/day) rats were tolerant to the effects of diazepam to increase Social Interaction in the low light unfamiliar Test condition of the Social Interaction Test of anxiety. When they were Tested 24 h after the last of 21 injections they showed significant decreases in Social Interaction, indicating an anxiogenic withdrawal response. However, the Social Interaction scores of rats Tested 48 h after withdrawal from diazepam treatment were no longer different from those of the control group. The decreased Social Interaction, indicating increased anxiety, detected 24 h after withdrawal of diazepam (21 daily injections of 0.5 or 2 mg/kg), could be reversed by the usual daily diazepam dose (0.5 or 2 mg/kg, respectively) or by baclofen (0.5 or 1 mg/kg). Baclofen (2 mg/kg) was sedative in both control treated and diazepam-dependent rats, but was ineffective at reversing the decrease in Social Interaction seen after diazepam withdrawal. Possible sites of action mediating these effects of baclofen are discussed, and it is suggested that either post-synaptic GABAB sites in the hippocampus are involved or that the reversal of the decreased Social Interaction detected on withdrawal of diazepam treatment is due to a baclofen-mediated inhibition of 5-HT release in the hippocampus.
Luis E. Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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stimulation of benzodiazepine receptors in the dorsal hippocampus and median raphe reveals differential gabaergic control in two animal Tests of anxiety
European Journal of Neuroscience, 1998Co-Authors: Luis E. Gonzalez, Abdel-mouttalib Ouagazzal, Sandra E. FileAbstract:The effects of pharmacological challenges to the benzodiazepine receptors in the dorsal hippocampus and median raphe nucleus were investigated in the Social Interaction and the elevated plus-maze Tests of anxiety in rats. In the Social Interaction Test, bilateral administration of midazolam (1 and 2 micrograms), into the dorsal hippocampus had anxiolytic effects; flumazenil (500 ng) was silent, but was able to antagonize the anxiolytic effects of midazolam (2 micrograms). In the Social Interaction Test, midazolam was also anxiolytic when infused into the median raphe nucleus; flumazenil (100 and 500 ng) increased locomotor activity, but did not change anxiety measures. As an anatomical control, midazolam (1 and 2 micrograms) was infused into the adjacent pontine reticular nucleus, and was without effect. In contrast to the Social Interaction Test, local infusion of midazolam (1 and 2 micrograms) and flumazenil (100 and 500 ng) into either the dorsal hippocampus or the median raphe nucleus failed to change anxiety measures in the elevated plus-maze (trials 1 and 2). These results show that stimulation of the benzodiazepine receptors in the hippocampus or the median raphe nucleus leads to anxiolytic effects in the Social Interaction Test, but not in the elevated plus-maze. It would therefore appear that the two Tests detect different types of anxiety that are differentially modulated by GABAA-benzodiazepine receptors in the dorsal hippocampus and the median raphe nucleus.
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evidence that the median raphe nucleus dorsal hippocampal pathway mediates diazepam withdrawal induced anxiety
Psychopharmacology, 1997Co-Authors: Nick Andrews, Luis E. Gonzalez, Cathy Fernandes, Sandra E. File, Nicholas M. BarnesAbstract:On the basis of our previous series of experiments we had postulated that the increased anxiety that occurred during diazepam withdrawal was mediated by increased 5-HT release in the hippocampus. The present series of experiments provide evidence for a major role of the median raphe nucleus (MRN) dorsal hippocampal pathway. Rats were treated once daily for 21 days with diazepam (2 mg/kg IP) and then Tested after 24 h withdrawal in the Social Interaction Test of anxiety. Relative to chronically vehicle treated animals, those withdrawn from diazepam were significantly more anxious and had significantly greater K+-evoked release of [3H]-5-hydroxytryptamine (5-HT) from slices of dorsal and of ventral regions of the hippocampus. Estimation of extracellular concentrations of 5-HT within the dorsal hippocampus, using in-vivo microdialysis, showed doubling in the levels of 5-HT in the rats withdrawn from chronic diazepam treatment. This just failed to reach significance, but 33% of the rats showed dramatic increases (650%). It was not possible to Test these animals in the Social Interaction Test, but it is proposed that only the diazepam-withdrawn rats with raised extracellular levels of 5-HT would have displayed increased anxiety. 5-HT1A receptor agonists injected into the MRN decrease the MRN firing rate, and hence the release of 5-HT in the dorsal hippocampus. As a further Test of our hypothesis, we examined the effects of MRN injection of the 5-HT1A receptor agonist, 8-OH DPAT, on animals withdrawn from diazepam and Tested in the low light familiar condition of the Social Interaction Test. 8-OH DPAT (50–200 ng) dose-dependently reversed the anxiogenic effect of diazepam withdrawal, while having no effects in chronic vehicle-treated animals. These results provide clear evidence that the MRN-dorsal hippocampal 5-HT pathway is at least one of the pathways playing an important role in mediating diazepam withdrawal-induced anxiety.
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5 ht1a and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the Social Interaction Test but not in the elevated plus maze
Brain Research, 1996Co-Authors: Luis E. Gonzalez, Nick Andrews, Sandra E. FileAbstract:In order to investigate the role of the 5-HT1A receptors of the amygdala in modulating anxiety, rats were implanted with bilateral cannulae aimed at the basolateral nucleus of the amygdala complex and infused with either artificial cerebrospinal fluid (aCSF) or the selective 5-HT1A receptor agonist 8-OH-DPAT (50-200 ng) and Tested in two animal models of anxiety. In the elevated plus-maze Test, no significant effects were detected in this dose range. In contrast, 8-OH-DPAT caused an overall reduction in levels of Social investigation, thus indicating anxiogenic actions in the Social Interaction Test. At 50 ng, 8-OH-DPAT had a selective action on anxiety, while at 200 ng there was a concomitant reduction in locomotor activity and, in some animals, signs of the 5-HT1A syndrome. Evidence that the anxiogenic effect of 8-OH-DPAT (50 ng) was due to activation of 5-HT1A receptors came from the finding that (-)-tertatolol, a 5-HT1A receptor antagonist, reversed this effect at a dose (1.5 micrograms) which was silent when given alone. The benzodiazepine receptor agonist, midazolam (1 and 2 micrograms) was bilaterally administered into the basolateral nucleus of the amygdala and evoked clear-cut anxiolytic effects in the Social Interaction Test. These data indicate that the agonist activation of post-synaptic 5-HT1A receptors in the basolateral nucleus of the amygdala may produce anxiogenic effects, while agonist activation of BDZ receptors in the same areas evokes anxiolytic effects. Our results from the Social Interaction Test are similar to those previously reported from Tests of anxiety using punished paradigms, but contrast with those found in the elevated plus-maze. Thus, it is concluded that either the two Tests have different sensitivities to midazolam and 8-OH-DPAT or more intriguingly, the Tests are evoking fundamentally different states of anxiety, with that evoked by the plus-maze being mediated via brain areas or receptors different from those studied here.
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5 ht1a receptors in the median raphe nucleus and dorsal hippocampus may mediate anxiolytic and anxiogenic behaviours respectively
European Journal of Pharmacology, 1994Co-Authors: Nick Andrews, Luis E. Gonzalez, Sandy Hogg, Sandra E. FileAbstract:The behavioural response of rats in the high light unfamiliar condition of the Social Interaction 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 μg) into the median raphe nucleus or dorsal hippocampus. In the median raphe nucleus, 8-OH-DPAT (200 ng) significantly increased Social Interaction without changing locomotor activity; lower doses were inactive. In the dorsal hippocampus, bilateral injection of 8-OH-DPAT (100 ng) significantly decreased Social Interaction, without effect on locomotor activity; both 50 and 100 ng significantly changed grooming. Tertatolol had no effect on Social Interaction following administration to the median raphe nucleus, but significantly increased locomotor activity. Bilateral injection of tertatolol into the dorsal hippocampus decreased Social Interaction and changed grooming. These effects are similar to those of 8-OH-DPAT suggesting tertatolol may have 5-HT1A receptor agonist properties. In conclusion, the findings of this study demonstrate that 5-HT1A somatodendritic autoreceptors and post-synaptic receptors mediate anxiolytic and anxiogenic effects, respectively, in the Social Interaction Test.
Frank Samsdodd - One of the best experts on this subject based on the ideXlab platform.
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effects of diazepam citalopram methadone and naloxone on pcp induced stereotyped behaviour and Social isolation in the rat Social Interaction Test
Neuroscience & Biobehavioral Reviews, 1998Co-Authors: Frank SamsdoddAbstract:Abstract Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. In the Social Interaction Test PCP induces stereotyped behaviour and Social isolation in rats, and these behaviours can be inhibited by antipsychotic drugs. In order to further evaluate the predictive validity of this model of schizophrenia the anxiolytic diazepam (0.02–17.5 μmol/kg; 0.005–5.0 mg/kg), the antidepressant citalopram (0.62–19.8 μmol/kg; 0.3–4.0 mg/kg), the opioid agonist methadone (0.36–5.8 μmol/kg; 0.13–2.0 mg/kg) and the opioid antagonist naloxone (0.34–22.0 μmol/kg; 0.13–8.0 mg/kg) were Tested as examples of drugs without antipsychotic activity. The experiments demonstrated that these compounds did not specifically inhibit the behavioural effects of PCP. So far only antipsychotic drugs have been able to specifically inhibit the PCP-induced behaviours.
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effects of dopamine agonists and antagonists on pcp induced stereotyped behaviour and Social isolation in the rat Social Interaction Test
Psychopharmacology, 1998Co-Authors: Frank SamsdoddAbstract:Phencyclidine (PCP) can induce a model psychosis in humans that resembles an acute schizophrenic psychosis. In animal models of schizophrenia, PCP induces locomotor hyperactivity, stereotyped behaviour and Social isolation, and the purpose of the present study was to describe the ability of dopamine agonists and antagonists to mimic or interact with these PCP-induced behaviours in rats. The compounds were administered daily for 3 days in combination with vehicle or 2.0 mg/kg PCP and the rats were Tested in the Social Interaction Test on the last day of drug administration. The study showed that D1-agonists with relative differences in efficacy at the DA-stimulated adenylate cyclase had limited effects on the PCP-induced behaviours, whereas the D1-antagonist SCH 23391 could alleviate the PCP-induce Social isolation following daily treatment for 3 days. However, following long-term treatment for 21 days, the rats develop tolerance to this effect. These data thus suggested that the D1-receptor system only had a modulatory effect on PCP. In contrast, the D2-receptor family may be more directly involved, because the D2/D3/D4-agonist quinpirole could mimic and potentiate the PCP-induced deficits in Social behaviour, and the D2/D3-antagonist (-)sulpiride could alleviate the PCP-induced stereotyped behaviour and Social isolation. However, a D4-antagonist did not affect the behaviour of vehicle- and PCP-treated rats, suggesting that this system plays a less direct role in the behavioural effects of PCP. In general, however, the effects of SCH 23391, quinpirole and (-)sulpiride on the PCP-induced behaviours were mirrored in the vehicle-treated control groups and it is therefore possible that non-specific effects may have been important.
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effect of novel antipsychotic drugs on phencyclidine induced stereotyped behaviour and Social isolation in the rat Social Interaction Test
Behavioural Pharmacology, 1997Co-Authors: Frank SamsdoddAbstract:Phencyclidine (PCP) induces stereotyped behaviour and Social isolation in rats; comparisons with clinical observations have suggested that these behaviours may mimic certain aspects of the positive and the negative symptoms, respectively, of an acute schizophrenic episode. Novel antipsychotics are effective in treating the positive symptoms in schizophrenic patients and have also shown some promise in treating the negative symptoms. In the present study the effects of the novel antipsychotics remoxipride (2.5-20 mg/kg), risperidone (0.02-0.63 mg/kg), sertindole (0.01-2.5 mg/kg), olanzapine (0.16-2.5 mg/kg) and quetiapine (0.16-10 mg/kg) on PCP-induced behaviours were determined. The drugs were administered daily for 3 or 21 days in combination with vehicle or 2.0 mg/kg of PCP for the last 3 days of the administration regime, and the rats were Tested using the Social Interaction Test. The antipsychotic drugs all reliably reduced the level of PCP-induced stereotyped behaviour and had distinct effects on PCP-induced Social isolation. Comparison with clinical findings suggests that the PCP-induced behaviours respond to treatment with antipsychotic drugs in a manner that correlates well with clinical observations, and that this animal model of schizophrenia may be useful for evaluating novel drug candidates. However, the study also showed that additional experiments are required to determine the specificity by which antipsychotic drugs alleviate PCP-induced behaviours because most of the drugs also affected considerably the behaviour of the control animals.
Survjit Cheeta - One of the best experts on this subject based on the ideXlab platform.
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Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the Social Interaction Test in gerbils
Brain research, 2001Co-Authors: Survjit Cheeta, Sonia Tucci, Nadia M. J. Rupniak, J Sandhu, A.r Williams, Sandra E. FileAbstract:The gerbil Social Interaction Test has previously detected anxiolytic effects of nicotine and diazepam. In the present study, the high affinity substance P (NK1) receptor antagonist L-760735 (3 mg/kg) significantly increased the time spent in Social Interaction, whereas its low affinity analogue L-781773 (3 mg/kg) was without effect. Diazepam (0.1 mg/kg) and the 5-HT1A receptor agonist 8-OH-DPAT (0.003 and 0.01 mg/kg) also increased Social Interaction, whereas an acute dose of the selective serotonin re-uptake inhibitor fluoxetine (10 mg/kg) decreased the time spent in Social Interaction. Diazepam (0.1 mg/kg) significantly increased locomotor activity, but this effect was independent of the increase in Social Interaction. The other drugs Tested were without effect on locomotor activity. The present findings suggest that the gerbil Social Interaction may well provide a useful assay for detecting both anxiolytic and anxiogenic compounds, and suggests that the high affinity NK1 receptor antagonist L-760735 may prove to be useful as an anxiolytic therapy.
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Social isolation modifies nicotine s effects in animal Tests of anxiety
British Journal of Pharmacology, 2001Co-Authors: Survjit Cheeta, Elaine E. Irvine, Sandra E. FileAbstract:These experiments determined whether the housing conditions of rats influenced the effects of nicotine in two animal Tests of anxiety, Social Interaction and elevated plus-maze Tests. In animals housed singly for 7 days, (−)nicotine (0.025 mg kg−1 s.c.) was ineffective, but 0.05, 0.1 and 0.25 mg kg−1 (s.c.) significantly increased the time spent in Social Interaction, without changing locomotor activity, thus indicating anxiolytic actions. (−)Nicotine (0.45 mg kg−1 s.c.) significantly reduced Social Interaction, indicating an anxiogenic effect. However, in group-housed animals, (−)nicotine (0.025 mg kg−1 s.c.) had a significant anxiolytic effect in the Social Interaction Test, but 0.01, 0.05, 0.1, 0.25 and 0.45 mg kg−1 were ineffective. (−)Nicotine (1 mg kg−1) reduced motor activity and Social Interaction in the group-housed animals. In the elevated plus-maze, the time-course and the dose-response curve to nicotine were investigated. In both singly- and group-housed rats, (−) nicotine (0.1 – 0.45 mg kg−1 s.c.) decreased the per cent entries into, and per cent time spent on, the open arms, indicating anxiogenic effects. The housing condition influenced the time course, with significant effects at 5 and 30 min after injection in group-housed rats, and significant effects at 30 and 60 min in singly-housed rats. In the Social Interaction Test there was no difference in the scores of the first and last rats removed from group cages, whereas the order of removal from the cages did affect the scores in the elevated plus-maze. These results provide further evidence that the two animal Tests model distinct states of anxiety, and show how Social isolation powerfully modifies both anxiolytic and anxiogenic effects of nicotine. British Journal of Pharmacology (2001) 132, 1389–1395; doi:10.1038/sj.bjp.0703991
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Development of tolerance to nicotine's anxiogenic effect in the Social Interaction Test.
Brain research, 2001Co-Authors: Elaine E. Irvine, Survjit Cheeta, Sandra E. FileAbstract:The purpose of the present experiment was to explore the role of the dorsal hippocampus in mediating the development of tolerance to the anxiogenic effect of nicotine in the Social Interaction Test of anxiety, and to determine whether tolerance develops to the effects of nicotine on [3H]-5-HT release in this area. Nicotine (1 microg) administered bilaterally into the dorsal hippocampus significantly reduced the time spent in Social Interaction in vehicle pre-treated rats, indicating an anxiogenic effect, but tolerance to this effect was seen in the rats pre-treated for 6 days with s.c. nicotine (0.1 mg/kg/day). In rats that had been pre-treated with vehicle for 6 days, nicotine (50-200 microM), significantly stimulated [3H]-5-HT release from dorsal hippocampal slices. This stimulation was significantly reduced in rats pre-treated with nicotine (0.1 mg/kg/day) for 6 days, indicating the development of tolerance to the effects of nicotine on 5-HT release. This suggests that tolerance to the anxiogenic effect of nicotine administered into the dorsal hippocampus could be mediated by a reduction in the nicotine enhancement of 5-HT release in this area.
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the dorsal raphe nucleus is a crucial structure mediating nicotine s anxiolytic effects and the development of tolerance and withdrawal responses
Psychopharmacology, 2001Co-Authors: Survjit Cheeta, Elaine E. Irvine, Paul J. Kenny, Sandra E. FileAbstract: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 raphe 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 (2.5–4000 ng) following DRN infusion, and whether co-administration of the specific 5-HT1A receptor antagonist WAY 100635 could antagonise the anxiolytic action of nicotine. We then examined the effects of intra-DRN nicotine (2.5–7 ng) following six daily injections of subcutaneous (s.c.) (-)-nicotine (0.1 mg/kg). Finally, we examined whether s.c. or intra-DRN (-)-nicotine could antagonise the anxiogenic response seen 72 h after the termination of 7 days of nicotine treatment. Results: Acute nicotine administration into the DRN produced dose-related effects: low doses (2.5–10 ng) induced an anxiolytic effect, intermediate doses were behaviourally silent (100–1000 ng), and an anxiogenic effect was seen following administration of a high dose (4 µg). The anxiolytic effect of (-)-nicotine (5 ng) was reversed by co-administration of a behaviourally inactive dose of WAY 100635 (200 ng). Following 6 days of treatment with s.c. 0.1 mg/kg per day (-)-nicotine, tolerance developed to its anxiolytic action in the DRN. Rats withdrawn for 72 h following this chronic treatment showed an anxiogenic response which was reversed by (-)-nicotine injected s.c. (0.1 mg/kg) or into the DRN (5 ng). 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 72 h after withdrawal from chronic nicotine, this suggests that an oppositional, compensatory mechanism is mediating the tolerance.
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diazepam and nicotine increase Social Interaction in gerbils a Test for anxiolytic action
Brain Research, 2001Co-Authors: Sandra E. File, Survjit Cheeta, Chioma AkaneziAbstract:The effects of two drugs with anxiolytic actions, diazepam (0.1, 0.3 and 1 mg/kg) and nicotine (0.1 and 0.5 mg/kg) were examined on the time spent in Social Interaction by pairs of male gerbils. In a Test arena lit by high light, diazepam (0.1 mg/kg) increased Social Interaction, without changing locomotor activity. Diazepam (0.3 and 1 mg/kg) produced a dose-related increase in locomotor activity, which reached significance at the higher dose. Nicotine produced a dose-related increase in Social Interaction, which reached significance at 0.5 mg/kg, but was without effect on locomotor activity. The specific increases in Social Interaction observed with diazepam and nicotine are similar to those seen in the well-validated Social Interaction Test of anxiety in rats and suggest that Social Interaction in gerbils may also be used to screen for anxiolytic action of novel compounds.