Generalization of clozapine as compared to other antipsychotic agents to a discriminative stimulus elicited by the serotonin (5-HT)2A antagonist, MDL100,907

Employing a two-lever, food-reinforced FR10 procedure, rats were trained to recognize a discriminative stimulus (DS) elicited by the 5-HT2A receptor antagonist and potential antipsychotic agent, MDL100,907 (0.16 mg/kg, i.p.). In generalization tests, by analogy to MDL100, 907 itself (Effective Dose(50) (ED50), 0.002 mg/kg, s.c.), the 'atypical' antipsychotic, clozapine, which displays high affinity for 5-HT2A as compared to D-2 receptors, dose-dependently and fully generalized to MDL100,907 (ED50, 0.2 mg/kg, s.c.). S16924 (0.05 mg/kg, s.c.), S18327 (0.09 mg/kg, s.c.), quetiapine (1.8 mg/kg, s.c.), risperidone (0.02 mg/kg, s.c.) and ziprasidone (0.01 mg/kg, s.c.), antipsychotics which possess-like clozapine-marked affinity for 5-HT2A versus D-2 receptors, also generalized to MDL100,907. In distinction, raclopride, an antipsychotic which selectively interacts with D-2 versus 5-HT2A receptors, did not display significant generalization. Interestingly, haloperidol, which shows only modest affinity for 5-HT2A versus D-2 sites, generalized to MDL100,907 (ED50, 0.02 mg/kg, s.c.). In light of the antagonist properties of haloperidol, clozapine and all other antipsychotics tested (except raclopride) at alpha(1)-adrenoceptors (ARs), the selective alpha(1)-AR antagonists, prazosin and WB4101, were examined. Both dose-dependently and fully generalized to MDL100,907 (ED(50)s 0.07 and 0.11 mg/kg, s.c., respectively). At doses showing pronounced generalization to MDL100,907, the only drugs which significantly suppressed response rates were haloperidol and, weakly, quetiapine. Raclopride also markedly decreased response rates. In conclusion, the antipsychotic agents, clozapine, ziprasidone, risperidone, S16924, S18327, quetiapine and haloperidol, all generalized to a DS elicited by MDL100,907. While D-2 receptors are not implicated in their actions, in addition to antagonist properties at 5-HT2A receptors, blockade of alpha(1)-ARs and other, as yet unidentified, mechanisms may be involved. These data underpin interest in MDL100,907 as a potential antipsychotic agent. (C) 2003 Elsevier Science Ltd. All rights reserved.