Evaluation of the effects of α2 adrenoceptor antagonism with the D2 receptor antagonist raclopride on conditioned avoidance responding in rats.

The α2 adrenoceptor antagonist idazoxan, when combined with a subeffective dose of the D2 receptor antagonist raclopride or other D2 receptor antagonists, produces inhibition of conditioned avoidance responding (CAR) in rats, an effect predictive of antipsychotic effects. In other models, this treatment combination indicates putative atypical antipsychotic effects as well, and has led to a α2/D2 receptor hypothesis for atypicality. However, this hypothesis would be better supported if other α2 adrenoceptor antagonists were investigated and the role of the alternative mechanisms, particularly 5-HT1A receptor agonism, for the behavioral effects of idazoxan were evaluated. This study sought to further test the α2/D2 receptor hypothesis by assessing the effects of α2, D2 and 5-HT1A receptor ligands on CAR in rats. Raclopride significantly reduced CAR. Administration of idazoxan or the α2 adrenoceptor antagonist yohimbine with a subeffective dose of raclopride also significantly reduced CAR. Pretreatment with the 5-HT1A receptor antagonist WAY100635 failed to significantly reverse the inhibition of CAR produced by the idazoxan and raclopride treatment combination. To the extent that 5-HT1A receptor antagonism failed to block the effects of idazoxan in combination with raclopride on CAR, α2 adrenoceptor antagonism alone appears to potentiate the putative antipsychotic effects produced through D2 receptor antagonism.