Does Antagonism at 5-HT _2A Receptors Potentiate D2 Blockade-Induced Disruption of Conditioned Avoidance Response?

Existing evidence in the literature shows that antagonism at 5-HT _2A receptors potentiates D2 antagonisminduced disruption of conditioned avoidance response (CAR), a behavioral index of antipsychotic activity, suggesting that combining 5-HT _2A antagonism with D2 antagonism may confer an enhanced antipsychotic effect. The present study reexamined this issue and further investigated other behavioral effects of drug- drug interaction, mainly the conditioned drug effect (via drug- drug conditioning) and 5-HT _2A antagonism's modulation on antipsychotic-induced sensitization (an enhanced avoidance disruption). Well-trained adult male Sprague-Dawley rats were first repeatedly tested for 7 days under haloperidol (HAL; 0.05 mg/kg, subcutaneous [sc], a typical antipsychotic drug with potent D2 antagonism), MDL100907 (0.5 and 1.0 mg/kg, sc, a selective 5-HT _2A antagonist), combined MDL100907 and HAL, or vehicle control, followed by one challenge test under MDL100907 (0.5 mg/kg) to assess the conditioned drug effect and one challenge test under HAL (0.025 mg/kg) to assess HAL sensitization. Results showed that MDL100907 by itself had no effect on CAR. Importantly, MDL100907 treatment did little to alter the acute and sensitized effects of HAL-induced (0.05 mg/kg, sc) suppression of CAR under various treatment conditions. Repeated pairing of MDL100907 (1.0 mg/kg) with HAL rendered MDL100907 itself to exhibit an "acquired" CAR disruptive effect through a drug- drug conditioning process. These results do not support the notion that 5-HT _2A receptor blockade enhances the antipsychotic-like effects of typical antipsychotic drugs, although they do highlight the importance of drug- drug conditioning process in altering drug efficacy in polypharmacy.