Brain-penetrant neurotensin NTS1 receptor agonists produce antipsychotic drug-like effects in animal models, including inhibition of conditioned avoidance responding and reversal of psychostimulant-induced hyperactivity and stereotypy. Allosteric interactions between NTS1 receptors and dopamine D2 receptors may account for some of these antipsychotic effects. In order to determine the role that dopamine receptors may play in the behavioral effects produced by activation of NTS1 receptors, a drug discrimination approach was used in rats to evaluate the potential mediation of NTS1 receptor agonist stimulus effects by dopamine D1 and D2 receptors. Rats were trained to discriminate either the NTS1 receptor agonist PD149163, the D1 receptor agonist SKF81297, or the D2 receptor agonist quinpirole from vehicle in a two choice drug discrimination task. Full stimulus generalization occurred from PD149163 to the typical antipsychotic drug and D2 receptor-preferring antagonist haloperidol. However, stimulus generalization did not occur from SKF81297 or quinpirole to PD149163. The discriminative cue for SKF91297 and quinpirole was fully blocked the D1 receptor antagonist SCH23390 and the D2/3 receptor antagonist raclopride, respectively. Cross generalization did not occur between SKF91297 and quinpirole. Based on these findings, the stimulus effects of PD149163 may be mediated, in part, through D2 receptor antagonism, but this may only be evident when PD149163 is used as the training drug.

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...