title: Cocaine dysregulates opioid gating of GABA neurotransmission in the ventral pallidum.
abstract: The ventral pallidum (VP) is a target of dense nucleus accumbens projections. Many of these projections coexpress GABA and the neuropeptide enkephalin, a δ and μ opioid receptor (MOR) ligand. Of these two, the MOR in the VP is known to be involved in reward-related behaviors, such as hedonic responses to palatable food, alcohol intake, and reinstatement of cocaine seeking. Stimulating MORs in the VP decreases extracellular GABA, indicating that the effects of MORs in the VP on cocaine seeking are via modulating GABA neurotransmission. Here, we use whole-cell patch-clamp on a rat model of withdrawal from cocaine self-administration to test the hypothesis that MORs presynaptically regulate GABA transmission in the VP and that cocaine withdrawal changes the interaction between MORs and GABA. We found that in cocaine-extinguished rats pharmacological activation of MORs no longer presynaptically inhibited GABA release, whereas blocking the MORs disinhibited GABA release. Moreover, MOR-dependent long-term depression of GABA neurotransmission in the VP was lost in cocaine-extinguished rats. Last, GABA neurotransmission was found to be tonically suppressed in cocaine-extinguished rats. These substantial synaptic changes indicated that cocaine was increasing tone on MOR receptors. Accordingly, increasing endogenous tone by blocking the enzymatic degradation of enkephalin inhibited GABA neurotransmission in yoked saline rats but not in cocaine-extinguished rats. In conclusion, our results indicate that following withdrawal from cocaine self-administration enkephalin levels in the VP are elevated and the opioid modulation of GABA neurotransmission is impaired. This may contribute to the difficulties withdrawn addicts experience when trying to resist relapse.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol and Alcoholism, Rockville, Maryland 20892, Pharmaleads SAS, 75013 Paris, France, and Université Paris-Descartes, 75006 Paris, France.
authors.forename: Yonatan M
authors.initials: YM
authors.lastname: Kupchik
authors.forename: Michael D
authors.initials: MD
authors.lastname: Scofield
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kalivas
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D005917:Globus Pallidus / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D005680:gamma-Aminobutyric Acid; D003042:Cocaine
keywords: addiction; cocaine; electrophysiology; enkephalin; ventral pallidum; μ opioid receptor