Blockade of the Serotonin 5-HT2A Receptor Suppresses Cue-Evoked Reinstatement of Cocaine-Seeking Behavior in a Rat Self-Administration Model

The serotonin 5-HT2A receptor (5-HT2AR) may play a role in reinstatement of drug-seeking. This study investigated the ability of a selective 5-HT2AR antagonist to suppress reinstatement evoked by exposure to cues conditioned to cocaine self-administration. Cocaine self-administration (0.75 mg/kg/0.1 mL/6 s infusion; FR 4) was trained in naive, free-fed rats to allow interpretation of results independent from changes related to food deprivation stress. Pretreatment with the selective 5-HT2AR antagonist M100907 (volinanserin) failed to reduce rates of operant responding for cocaine infusions. On the other hand, M100907 (0.001-0.8 mg/kg ip) significantly suppressed the cue-induced reinstatement of cocaine-seeking behavior following extinction; effective M100907 doses did not alter operant responding for cues previously associated with sucrose self-administration. Importantly, a greater magnitude of active lever presses on the initial extinction session (high extinction responders) predicted the maximal susceptibility to M100907-induced suppression of cue-evoked reinstatement. The findings indicate that blockade of the 5-HT2AR attenuates the incentive-motivational effects of cocaine-paired cues, particularly in high extinction responders, and suggests that M100907 may afford a therapeutic advance in suppression of cue-evoked craving and/or relapse.