Discriminative stimulus properties of idazoxan: mediation by both α2 adrenoceptor antagonism and 5‐HT1A receptor agonism

Abstract

AbstractIdazoxan is reference α2 adrenoceptor antagonist and has been extensively used preclinically to support the “α2/D2 receptor hypothesis” for atypical antipsychotic effects. However, previous studies have shown that the anticataleptic and discriminative stimulus properties of idazoxan may be mediated by 5‐HT1A receptor agonism. The present study was conducted to further assess the role of α2 adrenoceptor antagonism and 5‐HT1A receptor agonism in the discriminative stimulus properties of idazoxan using a 5.0‐mg/kg training dose in rats. Idazoxan produced full‐stimulus generalization to itself, the α2 adrenoceptor antagonist yohimbine, and the 5‐HT1A receptor partial agonist, 8‐OH‐DPAT. Both the α2 adrenoceptor agonists clonidine and guanfacine, and the 5‐HT1A receptor antagonist WAY100635, partially blocked the discriminative stimulus effects of idazoxan. Finally, partial stimulus generalization occurred to the atypical antipsychotic drug clozapine. On the basis of these findings, both α2 adrenoceptor antagonism and 5‐HT1A receptor agonism appear to contribute to the discriminative stimulus effects of idazoxan. Thus, the role of 5‐HT1A receptor agonism should be considered when evaluating the behavioral effects of idazoxan. Drug Dev Res 71: 261–267, 2010. © 2010 Wiley‐Liss, Inc.