Does antagonism at 5-HT<sub>2A</sub> receptors potentiate D₂ blockade-induced disruption of conditioned avoidance response?

Existing evidence in the literature shows that antagonism at 5-HT2A receptors potentiates Dâ‚‚ antagonism-induced disruption of conditioned avoidance response (CAR), a behavioral index of antipsychotic activity, suggesting that combining 5-HT2A antagonism with Dâ‚‚ 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-HT2A 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-HT2A 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-HT2A 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. (PsycINFO Database Record (c) 2019 APA, all rights reserved)