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 m ight 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 re ceptor antagonist produces a robust antipsychotic-like effect in the condit ioned avoidance response (CAR) test. Electrophysiological and biochemical s tudies also show that 5-HT2A receptor antagonists can confer an atypical (c lozapine-like) profile an a D-2 receptor antagonist. Improved therapeutic e fficacy 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 sy mptoms still remains unclear. Using the CAR and the catalepsy (CAT) tests a s indices for antipsychotic activity and extrapyramidal side effect (EPS) l iability, respectively, the effects of the selective 5-HT2A receptor antago nist MDL 100,907 in combination with the DA D-2 receptor antagonists halope ridol or raclopride were studied in rats. Haloperidol (0.025 or 0.1 mg/kg s c, -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 t he 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 in effective doses of raclopride. Raclopride (1 mg/kg sc, - 30 min) alone prod uced a submaximal cataleptic response that was significantly enhanced by pr etreatment with MDL 100,907. The present results confirm and extend previou s results by showing that 5-HT2A receptor blockade can enhance the antipsyc hotic-like effects of a very low dose of a commonly used traditional antips ychotic. 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 .