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The four-plates test-retest paradigm to discriminate anxiolytic effects.

Ripoll N, Nic Dhonnchadha BA, Sébille V, Bourin M, Hascoët M

Neurobiologie de l'anxiété et de la dépression, Faculté de Médecine, EA 3256, 1 rue Gaston Veil, BP 53508, 44035 Nantes cedex 01, France.

RATIONALE: Animal models of anxiety such as the four-plates test (FPT) enable the detection of an anxiolytic effect not only of benzodiazepines (BZDs) but also of other non-BZD anxiolytic compounds such as the antidepressants paroxetine and venlafaxine. Retesting mice in animal models of anxiety markedly alters the behavioural profile of various drugs. OBJECTIVES: The aim of this study was first to investigate the function of GABA(A)/BZD receptor and passive avoidance acquisition in the FPT "test-retest". The second aim of this study was to evaluate the capacity of the FPT to discriminate BZDs from other non-BZD anxiolytics in experienced mice. METHODS: The FPT was performed in naive and experienced mice (submitted to the test 24 h previously). The drugs studied were two BZDs, diazepam (1 mg/kg) and alprazolam (0.25 mg/kg); flumazenil, a GABA(A) receptor antagonist (8 mg/kg); atropine sulphate, a muscarinic cholinergic receptor antagonist (4 mg/kg) known for its amnesic properties; paroxetine, a selective serotonin reuptake inhibitor (4 and 8 mg/kg); venlafaxine, a serotonin and noradrenalin reuptake inhibitor (4 and 16 mg/kg); and DOI, a 5-HT2A agonist (1 mg/kg). RESULTS: Our results reveal an increase of anxiety (decrease of punished passages) in saline-experienced mice. Diazepam, alprazolam, paroxetine and venlafaxine did not prevent the increase in anxiety during retest, revealing a passive avoidance acquisition. Flumazenil did not modify the anxiogenic-like behaviour of experienced mice. In contrast, atropine seems to oppose the increase of anxiety; however, its effect is weak and disputable. DOI was the only anxiolytic compound able to oppose the decrease of punished passages of experienced mice. CONCLUSION: Anxiogenic behaviour on retesting indicates aversive learning. The protocol test-retest is unable to discriminate between the anxiolytic effect of BZDs from that of paroxetine or venlafaxine. However, this modified model may constitute a new tool to investigate other neural pathways implicated in anxiety.

Published 26 May 2005 in Psychopharmacology (Berl), 180(1): 73-83.
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