Blockade of 5-HT_2A receptors in the medial prefrontal cortex attenuates reinstatement of cue-elicited cocaine-seeking behavior in rats

Rationale: The action of serotonin (5-HT) at the 5-HT_2A receptor subtype is thought to be involved in cocaine-seeking behavior that is motivated by exposure to drug-associated cues and drug priming. 5-HT_2A receptors are densely clustered in the ventromedial prefrontal cortex (vmPFC), an area that plays a role in mediating cocaine-seeking behavior. Objectives: This study examined the hypothesis that M100907, a 5-HT_2A receptor antagonist, infused directly in the vmPFC attenuates cue- and cocaine-primed reinstatement of cocaine-seeking behavior. Methods: Rats trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues underwent extinction training during which operant responses produced no consequences. Once behavior extinguished, rats were tested for reinstatement of responding elicited by either response-contingent presentations of the cocaine-paired light/tone cues or by cocaine-priming injections (10 mg/kg, i.p.) within 1 min after pretreatment with microinfusions of M100907 (0.1, 0.3, 1.0, or 1.5 μg/0.2 μl/side) into the vmPFC. Results: Intra-vmPFC M100907 decreased cue-elicited reinstatement at the two highest doses (1.0 and 1.5 μg) but produced only a slight decrease in cocaine-primed reinstatement that was not dose dependent. The decrease in cue reinstatement was not likely due to impaired ability to respond since intra-vmPFC M100907 infusions had minimal effect on cocaine self-administration and no effect on cue-elicited sucrose-seeking behavior, or spontaneous or cocaine-induced locomotion. M100907 infusions into the adjacent anterior cingulate cortex had no effect on cue reinstatement. Conclusions: The results suggest that the blockade of 5-HT _2A receptors in the vmPFC selectively attenuates the incentive motivational effects of cocaine-paired cues.