title: Deficits in ventromedial prefrontal cortex group 1 metabotropic glutamate receptor function mediate resistance to extinction during protracted withdrawal from an extensive history of cocaine self-administration.
abstract: Anomalies in prefrontal cortex (PFC) function are posited to underpin difficulties in learning to suppress drug-seeking behavior during abstinence. Because group 1 metabotropic glutamate receptors (mGluRs) regulate drug-related learning, we assayed the consequences of extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) on the PFC expression of group 1 mGluRs and the relevance of observed changes for cocaine seeking. After protracted withdrawal, cocaine-experienced animals exhibited a time-dependent intensification of cue-induced cocaine-seeking behavior and an impaired extinction of this behavior. These behavioral phenomena were associated with a time-dependent reduction in mGluR1/5 expression within ventromedial PFC (vmPFC) of cocaine-experienced animals exposed to extinction testing but not in untested ones. Interestingly, pharmacological manipulations of vmPFC mGluR1/5 produced no immediate effects on cue-induced cocaine-seeking behavior but produced residual effects on a subsequent test for cocaine seeking. At 3 d withdrawal, cocaine-experienced rats infused intra-vmPFC with mGluR1/5 antagonists, either before or after an initial test for cocaine seeking, persisted in their cocaine seeking akin to cocaine-experienced rats in protracted withdrawal. Conversely, cocaine-experienced rats infused with an mGluR1/5 agonist before the initial test for cocaine-seeking at 30 d withdrawal exhibited a facilitation of extinction learning. These data indicate that cue-elicited deficits in vmPFC group 1 mGluR function mediate resistance to extinction during protracted withdrawal from a history of extensive cocaine self-administration and pose pharmacological stimulation of these receptors as a potential approach to facilitate learned suppression of drug-seeking behavior that may aid drug abstinence.
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California 93106-9660, USA.
authors.forename: Osnat
authors.initials: O
authors.lastname: Ben-Shahar
authors.forename: Arianne D
authors.initials: AD
authors.lastname: Sacramento
authors.forename: Bailey W
authors.initials: BW
authors.lastname: Miller
authors.forename: Sierra M
authors.initials: SM
authors.lastname: Webb
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Wroten
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Silva
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Caruana
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Gordon
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Ploense
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ditzhazy
authors.forename: Tod E
authors.initials: TE
authors.lastname: Kippin
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019970:Cocaine-Related Disorders / Q000503:physiopathology* / Q000523:psychology; D003216:Conditioning, Operant; D003463:Cues; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D007267:Injections; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D012008:Recurrence; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology* / Q000523:psychology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D008734:Methoxyhydroxyphenylglycol; C121465:6-methyl-2-(phenylethynyl)pyridine; C010117:3,4-dihydroxyphenylglycol