α2-Adrenoceptor Antagonists Reverse the 5-HT 2 Receptor Antagonist Suppression of Head-Twitch Behavior in Mice

Abstract

The α2-adrenoceptor agonist clonidine, as well as 5-HT 2 receptor antagonists, reportedly suppress 5-HT 2 receptor-mediated head-twitch behavior. We investigated the effect of α2-adrenoceptor antagonists on the suppressive action of 5-HT 2 receptor antagonists in mice pretreated with the noradrenaline toxin 6-hydroxydopamine (6-OHDA) or the 5-HT synthesis inhibitor p-chlorophenylalanine ( p-CPA). In normal mice, idazoxan (0.08-0.2 mg/kg, IP) or yohimbine (0.2-2.0 mg/kg, IP), both α2-adrenoceptor antagonists, had no effect on the head-twitch response caused by 5-methoxy- N,N-dimethyltryptamine (5-MeO-DMT; 16 mg/kg, IP), but idazoxan significantly enhanced the response at 0.5 mg/kg. On the other hand, these α2-adrenoceptor antagonists, at doses that had no effect on the basal number of head-twitches (idazoxan 0.2 mg/kg and yohimbine 0.5 mg/kg), significantly attenuated not only the suppressive effect of clonidine (0.01 mg/kg, IP) on head-twitch response but also that of the 5-HT 2 receptor antagonist ritanserin (0.03 mg/kg, IP). Moreover, idazoxan (0.2 mg/kg) also significantly reversed the inhibition by 0.01 mg/kg (IP) ketanserin, a selective 5-HT 2 receptor antagonist. Pretreatment with 6-OHDA plus nomifensine but not with p-CPA significantly attenuated the effect of idazoxan (0.2-0.5 mg/kg) on the ritanserin inhibition of the head-twitch response. Prazosin, an α1-adrenoceptor antagonist, dose-dependently suppressed the response, and the effect of prazosin (1.25 mg/kg) was significantly attenuated by 0.5 mg/kg idazoxan. These results indicate that endogenous noradrenaline is involved in the apparent antagonistic interaction between selective α2-adrenoceptor antagonists and 5-HT 2 receptor antagonists in the head-twitch response, and suggest that noradrenaline stimulation of α1-adrenoceptors may be involved in this apparent antagonism.