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-HT2A/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-HT2A available, it acts as agonist at all three 5-HT2 receptor subtypes (5-HT2A, 5-HT2B and 5-HT2C). The aim of this study was thus to investigate in the FPT test–retest paradigm, which 5-HT2 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-HT2B, BW 723C86 (1–16 mg/kg) and 5-HT2C, RO 60-0175 (0.25–4 mg/kg) have also been studied. Then, antagonism studies were conducted combinating the 5-HT2A receptor antagonist SR 46349B, the 5-HT2B/2C receptor antagonist SB 206553 or the selective 5-HT2C 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-HT2A receptors.