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

Abstract

Idazoxan is reference a 2 adrenoceptor antagonist and has been extensively used preclinically to support the ''a 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 a 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 a 2 adrenoceptor antagonist yohimbine, and the 5-HT 1A receptor partial agonist, 8-OH-DPAT. Both the a 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 a 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. r 2010 Wiley-Liss, Inc.Idazoxan (2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole) is a selective antagonist at a 2 adrenoceptors [Doxey et al., 1984;Millan et al., 2000]. In particular, idazoxan has been used evaluate the effects of a 2 adrenoceptor antagonism as a potential mechanism for atypical antipsychotic drug effects. While both typical and atypical antipsychotic drugs (APDs) offer improvements in positive symptoms of schizophrenia, atypical APDs are considered superior to typical APDs for the treatment of negative symptoms and cognitive impairment [Woodward et al., 2005] and carry a low risk of extrapyramidal side effects at therapeutically effective doses. The superior clinical efficacy of atypical antipsychotics may be due in part to elevations in prefrontal cortical dopamine (DA) levels, whereas typical antipsychotic drugs usually do not show this effect [Kuroki et al., 1999;Li et al., 2003;Moghaddam and Bunney, 1990;Rollema et al., 1997Rollema et al., , 2000. The ability of atypical antipsychotics to elevate prefrontal cortical DA levels appears to be due to blockade of 5-HT 2A or 5-HT 1A receptors combined with blockade of D 2 receptors, as systemic administration of the 5-HT 2A receptor antagonist M100907 with haloperidol [Liegeois et al., 2002] antagonist sulpiride cause significant increases in prefrontal cortical DA release.However, idazaxon has been shown to improve the efficacy of the typical antipsychotic fluphenazine in neuroleptic-resistant schizophrenic patients [Litman et al., 1993[Litman et al., , 1996 to an extent comparable to that in the atypical antipsychotic clozapine, in neurolepticresistant patients [Litman et al., 1996]. In rats, a treatment combination of idazoxan with a D 2 receptor antag...