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


OBJECTIVE
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.


CONCLUSIONS
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.
Ripoll
Nadège
N
Neurobiologie de l'anxiété et de la dépression, Faculté de Médecine, EA 3256, 1 rue Gaston Veil, BP 53508, 44035 Nantes cedex 01, France.
Nic Dhonnchadha
Bríd Aine
BA
Sébille
Véronique
V
Bourin
Michel
M
Hascoët
Martine
M
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D001285:Atropine / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D018678:Cholinergic Agents / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D004192:Discrimination, Psychological; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D017374:Paroxetine / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D058826:Serotonin 5-HT2 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride
D018759:Adrenergic Uptake Inhibitors; D000662:Amphetamines; D014151:Anti-Anxiety Agents; D001285:Atropine; D001569:Benzodiazepines; D018678:Cholinergic Agents; D003511:Cyclohexanols; D017374:Paroxetine; D011963:Receptors, GABA-A; D058826:Serotonin 5-HT2 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine