Implication of 5-HT2A subtype receptors in DOI activity in the four-plates test-retest paradigm in mice.
The four-plates test (FPT) is an animal model of anxiety which allows the detection of anxiolytic effect not only of benzodiazepines (BZDs) but also of other non-BZDs anxiolytic compounds such as antidepressants (ADs). Furthermore, DOI, a 5-HT(2A/2C) agonist, has been shown to exert an anxiolytic-like effect in this model. Retesting mice in animal models of anxiety (test-retest paradigm) induces an anxiogenic-like and a loss of anxiolytic-like effects in response to BZDs and ADs. On the contrary, DOI has been reported to oppose the fear potentiation induced by trial 1 in the FPT. Despite DOI is considered as one of the most selective 5-HT(2A) available, it acts as agonist at all three 5-HT(2) receptor subtypes (5-HT(2A), 5-HT(2B) and 5-HT(2C)). The aim of this study was thus to investigate in the FPT test-retest paradigm, which 5-HT(2) receptor subtype(s) was involved in the DOI-induced effect in experienced mice. The effect of DOI (0.25-4 mg/kg) and the agonists, 5-HT(2B), BW 723C86 (1-16 mg/kg) and 5-HT(2C), RO 60-0175 (0.25-4 mg/kg) have also been studied. Then, antagonism studies were conducted combinating the 5-HT(2A) receptor antagonist SR 46349B, the 5-HT(2B/2C) receptor antagonist SB 206553 or the selective 5-HT(2C) receptor antagonist RS 10-2221 (at the doses of 0.1 and 1 mg/kg) with the DOI (1 mg/kg). Our study shows that the BW 723C86 had no effect on retesting mice, whereas it exerted an anxiolytic-like effect in naive mice. By contrast to DOI, the RO 60-0175 had no effect neither in naive nor experienced mice. Furthermore, only the SR 46349B antagonized the DOI-induced anti-punishment effect. Diazepam included as a positive control also increased in each case the number of punished passages in naive mice. Our findings altogether also suggest that DOI exerts its anxiolytic-like effect in the FPT test-retest paradigm through 5-HT(2A) receptors.
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Research Group, EA 3256, Neurobiologie de l'anxiété et de la dépression, Faculté de Médecine, BP 53508, 1 rue Gaston Veil, F44035 Nantes Cedex 01, France.
Hascoët
Martine
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Bourin
Michel
M
D000662:Amphetamines / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D021122:Protein Subunits / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology*; D015203:Reproducibility of Results; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
C092430:1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine; C107821:8-(5-(5-amino-2,4-dimethoxyphenyl)-5-oxopentyl)-1,3,8-triazaspiro(4.5)decane-2,4-dione; D000662:Amphetamines; D007211:Indoles; D021122:Protein Subunits; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; D013449:Sulfonamides; D013876:Thiophenes; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine