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Blockade of 5-HT2A receptors in the medial prefrontal cortex attenuates reinstatement of cue-elicited cocaine-seeking behavior in rats

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Abstract

Rationale

The action of serotonin (5-HT) at the 5-HT2A receptor subtype is thought to be involved in cocaine-seeking behavior that is motivated by exposure to drug-associated cues and drug priming. 5-HT2A 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-HT2A 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-HT2A receptors in the vmPFC selectively attenuates the incentive motivational effects of cocaine-paired cues.

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Acknowledgments

The authors thank Suzanne Weber, Lindsey Robertson, Kenneth Thiel, Timothy Cheung, Natalie Peartree, Ryan Bastle, Marisa Ostos, and Anthony Shepard for their expert technical and surgical assistance. This research was supported by NIDA grant R01DA11064. The experiments performed comply with the current laws of the United States of America.

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None of the authors have any financial conflicts to disclose.

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Correspondence to Janet L. Neisewander.

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Pockros, L.A., Pentkowski, N.S., Swinford, S.E. et al. Blockade of 5-HT2A receptors in the medial prefrontal cortex attenuates reinstatement of cue-elicited cocaine-seeking behavior in rats. Psychopharmacology 213, 307–320 (2011). https://doi.org/10.1007/s00213-010-2071-9

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