Discriminative stimulus properties of idazoxan: mediation by both α₂ adrenoceptor antagonism and 5‐HT_1A receptor agonism

Abstract Idazoxan is reference α 2 adrenoceptor antagonist and has been extensively used preclinically to support the “α 2 /D 2 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‐HT 1A receptor agonism. The present study was conducted to further assess the role of α 2 adrenoceptor antagonism and 5‐HT 1A 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 α 2 adrenoceptor antagonist yohimbine, and the 5‐HT 1A receptor partial agonist, 8‐OH‐DPAT. Both the α 2 adrenoceptor agonists clonidine and guanfacine, and the 5‐HT 1A 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 α 2 adrenoceptor antagonism and 5‐HT 1A receptor agonism appear to contribute to the discriminative stimulus effects of idazoxan. Thus, the role of 5‐HT 1A receptor agonism should be considered when evaluating the behavioral effects of idazoxan. Drug Dev Res 71: 261–267, 2010. © 2010 Wiley‐Liss, Inc.