PT  - JOURNAL ARTICLE
AU  - Osnat Ben-Shahar
AU  - Arianne D. Sacramento
AU  - Bailey W. Miller
AU  - Sierra M. Webb
AU  - Melissa G. Wroten
AU  - Hannah E. Silva
AU  - Amanda L. Caruana
AU  - Evan J. Gordon
AU  - Kyle L. Ploense
AU  - Jennifer Ditzhazy
AU  - Tod E. Kippin
AU  - Karen K. Szumlinski
TI  - 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
AID  - 10.1523/JNEUROSCI.3710-12.2013
DP  - 2013 Jan 09
TA  - The Journal of Neuroscience
PG  - 495--506a
VI  - 33
IP  - 2
4099  - http://www.jneurosci.org/content/33/2/495.short
4100  - http://www.jneurosci.org/content/33/2/495.full
SO  - J. Neurosci.2013 Jan 09; 33
AB  - 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.