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.

TitleDeficits 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.
Publication TypeJournal Article
Year of Publication2013
AuthorsBen-Shahar O, Sacramento AD, Miller BW, Webb SM, Wroten MG, Silva HE, Caruana AL, Gordon EJ, Ploense KL, Ditzhazy J, Kippin TE, Szumlinski KK
JournalJ Neurosci
Volume33
Issue2
Pagination495-506a
Date Published2013 Jan 9
ISSN1529-2401
KeywordsAnimals, Blotting, Western, Cocaine-Related Disorders, Conditioning, Operant, Cues, Excitatory Amino Acid Antagonists, Extinction, Psychological, Injections, Male, Methoxyhydroxyphenylglycol, Prefrontal Cortex, Pyridines, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Recurrence, Self Administration, Substance Withdrawal Syndrome
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.

DOI10.1523/JNEUROSCI.3710-12.2013
Alternate JournalJ. Neurosci.
PubMed ID23303930
PubMed Central IDPMC3711633
Grant ListDA024038 / DA / NIDA NIH HHS / United States
DA027525 / DA / NIDA NIH HHS / United States
R01 DA024038 / DA / NIDA NIH HHS / United States