Antagonism at 5-HT2A receptors potentiates the effect of haloperidol in a conditioned avoidance response task in rats

High affinity for serotonin-2A (5-HT2A) over dopamine (DA) D-2 receptors is a leading hypothesis for clozapine's favorable therapeutic profile. Recent preclinical studies also indicate that a sufficient antipsychotic effect might be obtained by a combined high 5-HT2A/low D2 receptor blockade. Thus, addition of a 5-HT2A receptor antagonist to an ineffective dose of a D-2 receptor antagonist produces a robust antipsychotic-like effect in the conditioned avoidance response (CAR) test. Electrophysiological and biochemical studies also show that 5-HT2A receptor antagonists can confer an atypical (clozapine-like) profile an a D-2 receptor antagonist. Improved therapeutic efficacy by adjunctive 5-HT2A receptor antagonist treatment to a traditional D-2 receptor blocking regimen has been suggested. However, the ability of 5-HT2A receptor blockade to protect against, or ameliorate, parkinsonian symptoms still remains unclear. Using the CAR and the catalepsy (CAT) tests as indices for antipsychotic activity and extrapyramidal side effect (EPS) liability, respectively, the effects of the selective 5-HT2A receptor antagonist MDL 100,907 in combination with the DA D-2 receptor antagonists haloperidol or raclopride were studied in rats. Haloperidol (0.025 or 0.1 mg/kg sc, -30 min) produced a dose-dependent suppression of CAR. Pretreatment with MDL 100,907 (0.5, 1.0, or 1.5 mg/kg sc, - 60 min) enhanced and prolonged the haloperidol-induced suppression of CAR without escape failures. MDL 100,907 (1 mg/kg sc, - 60 min) had no effect on CAT when coadministered with ineffective doses of raclopride. Raclopride (1 mg/kg sc, - 30 min) alone produced a submaximal cataleptic response that was significantly enhanced by pretreatment with MDL 100,907. The present results confirm and extend previous results by showing that 5-HT2A receptor blockade can enhance the antipsychotic-like effects of a very low dose of a commonly used traditional antipsychotic. 5-HT2A receptor blockade does not, however, prevent EPS (CAT). The therapeutic advantage of this combination might, therefore, operate within a fairly narrow window. (C) 2001 Elsevier Science Inc. All rights reserved.