Stimulation of medial prefrontal cortex serotonin 2C (5-HT(2C)) receptors attenuates cocaine-seeking behavior.
Serotonin 2C receptor (5-HT(2C)R) agonists administered systemically attenuate both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior. To further elucidate the function of these receptors in addiction-like processes, this study examined the effects of microinfusing the 5-HT(2C)R agonist MK212 (0, 10, 30, 100 ng/side/0.2 microl) 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 before 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 before 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 cocaine-seeking behavior, but did not reliably affect cocaine self-administration. A subsequent experiment showed that the effects of MK212 (100 ng/side/0.2 microl) on reinstatement of extinguished cocaine-seeking behavior were blocked by co-administration of the 5-HT(2C)R antagonist SB242084 (200 ng/side/0.2 microl). 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-HT(2C)Rs in the mPFC attenuates the incentive motivational effects produced by sampling cocaine or exposure to drug-paired cues.
Department of Psychology, Arizona State University, Tempe, 85287-1104, USA.
Nathan S
NS
Pentkowski
Felicia D
FD
Duke
Suzanne M
SM
Weber
Lara A
LA
Pockros
Andrew P
AP
Teer
Elizabeth C
EC
Hamilton
Kenneth J
KJ
Thiel
Janet L
JL
Neisewander
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005108:Extinction, Psychological / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D007211:Indoles; D011719:Pyrazines; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C014896:6-chloro-2-(1-piperazinyl)pyrazine