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

J Neurosci. 2013 Jan 9;33(2):495-506a. doi: 10.1523/JNEUROSCI.3710-12.2013.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cocaine-Related Disorders / physiopathology*
  • Cocaine-Related Disorders / psychology
  • Conditioning, Operant
  • Cues
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology*
  • Injections
  • Male
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology*
  • Pyridines / administration & dosage
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / biosynthesis
  • Receptors, Metabotropic Glutamate / drug effects
  • Receptors, Metabotropic Glutamate / physiology*
  • Recurrence
  • Self Administration
  • Substance Withdrawal Syndrome / physiopathology*
  • Substance Withdrawal Syndrome / psychology

Substances

  • Excitatory Amino Acid Antagonists
  • Pyridines
  • Receptors, Metabotropic Glutamate
  • Methoxyhydroxyphenylglycol
  • 6-methyl-2-(phenylethynyl)pyridine
  • 3,4-dihydroxyphenylglycol