Stimulation of Medial Prefrontal Cortex Serotonin 2C (5-HT2C) Receptors Attenuates Cocaine-Seeking Behavior

Abstract

Serotonin 2C receptor (5-HT2CR) agonists administered systemically attenuate both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior. To further elucidate the role of these receptors in addiction-like processes, this study examined the effects of microinfusing the 5-HT2CR agonist MK212 (0, 10, 30, 100 ng/side/0.2µl) into the medial prefrontal cortex (mPFC) on cocaine self-administration and reinstatement of extinguished cocaine-seeking behavior. Male Sprague-Dawley rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. Once responding stabilized, rats received MK212 microinfusions prior to tests for maintenance of cocaine self-administration. Next, extinction training to reduce cocaine-seeking behavior, defined as responses performed without cocaine reinforcement available, occurred until low extinction baselines were achieved. Rats then received MK212 microinfusions prior to tests for reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-priming injections (10 mg/kg, i.p.) or response-contingent presentations of the cocaine-associated cues; operant responses during cocaine-primed reinstatement tests produced no consequences. MK212 microinfusions into the prelimbic and infralimbic, but not anterior cingulate, regions of the mPFC dose-dependently attenuated both cocaine-primed and cue-elicited reinstatement of extinguished cocaineseeking behavior but did not reliably affect cocaine self-administration. A subsequent experiment demonstrated that the effects of MK212 (100 ng/side/0.2µl) on reinstatement of extinguished cocaine-seeking behavior were blocked by co-administration of the 5-HT2CR antagonist SB242084 (200 ng/side/0.2µl). MK212 administered alone into the mPFC as a drug prime produced no discernable effects on cocaine-seeking behavior. These findings suggest that stimulation of 5-HT2CRs in the mPFC attenuates the incentive motivational effects produced by sampling cocaine or exposure to drug-paired cues.

The Serotonin 5-HT2C Receptor in Medial Prefrontal Cortex Exerts Rheostatic Control over the Motivational Salience of Cocaine-Associated Cues: New Observations from Preclinical Animal Research

“…In the Pentkowski et al (2010) study, microgram quantities of a drug were infused into one of three mPFC different subregions to activate the 5-HT 2C R signalosome before analysis of cocaine-or cue-evoked reinstatement. Pentkowski et al (2010) found that local stimulation of the 5-HT 2C R in the prelimbic and infralimbic subregions of the mPFC did not alter cocaine-taking, but did dose-dependently suppress reinstatement of cocaine-seeking behavior, an effect reversed by co-infusion of a selective 5-HT 2C R antagonist. Microinfusions of the 5-HT 2C R agonist into the anterior cingulate cortex were without effect in either paradigm.…”

“…Microinfusions of the 5-HT 2C R agonist into the anterior cingulate cortex were without effect in either paradigm. Thus, Pentkowski et al (2010) reveal that the control afforded by the mPFC 5-HT 2C R is specific to cocaine-seeking over cocaine-taking, and localized to more ventral mPFC subregions.These results are interpreted as reflecting 5-HT 2C Revoked decrements in the incentive-motivational value of the cocaine-primed and cue-elicited cocaine-seeking behavior. The mechanisms underlying suppression of cocaine-seeking by intra-mPFC infusion of a 5-HT 2C R agonist are likely to occur through stimulation of the 5-HT 2C R located on gamma-aminobutyric acid (GABA) interneurons or glutamate projection neurons that regulate mPFC output (Bubar and Cunningham, 2008) possibly via actions at the level of dopamine neurotransmission from the ventral tegmental area to limbic corticostriatal circuits known to be involved in goal-directed behaviors (Kalivas and Volkow, 2005).…”

“…The medial prefrontal cortex (mPFC) and associated circuits are particularly sensitive to plasticity incurred due to repeated pairing of environmental stimuli (eg, drug paraphernalia, etc) with exposure to abused drugs. These associations between environmental cues and drug-taking are essential drug-associated memories that can trigger conditioned emotional responses in addicts and 'craving' (desire for drug), oft cited to explain relapse to drug-seeking and drugtaking during abstinence.The cortical control of drug-seeking is the focus of a new study by Janet Neisewander and her colleagues reported in Neuropsychopharmacology (Pentkowski et al, 2010). These studies concentrate on cocaine dependence; cocaine abuse spirals to addiction in upwards of 15% of cocaine users and limited therapeutic options to suppress recidivism are available.…”

“…The cortical control of drug-seeking is the focus of a new study by Janet Neisewander and her colleagues reported in Neuropsychopharmacology (Pentkowski et al, 2010). These studies concentrate on cocaine dependence; cocaine abuse spirals to addiction in upwards of 15% of cocaine users and limited therapeutic options to suppress recidivism are available.…”

“…These studies concentrate on cocaine dependence; cocaine abuse spirals to addiction in upwards of 15% of cocaine users and limited therapeutic options to suppress recidivism are available. Pentkowski et al (2010) have uncovered a nuanced neural circuit that selectively restrains the frontocortical circuitry that controls drug-seeking behavior in rats. In the procedure employed here, intravenous catheters were surgically implanted and rats were trained to lever press to deliver an intravenous injection of cocaine plus several associated environmental cues (ie, light and tone, sound of infusion pump).…”