Behavioral and functional evidence of metabotropic glutamate receptor 2/3 and metabotropic glutamate receptor 5 dysregulation in cocaine-escalated rats: factor in the transition to dependence

Biol Psychiatry. 2010 Aug 1;68(3):240-8. doi: 10.1016/j.biopsych.2010.02.011. Epub 2010 Apr 22.


Background: Rats with extended daily cocaine access show escalating cocaine self-administration and behavioral signs of dependence. Regulation of glutamatergic transmission by metabotropic glutamate receptors has emerged as a mechanism in the addictive actions of drugs of abuse. We examined here whether neuroadaptive dysregulation of metabotropic glutamate receptor function is a factor in escalating cocaine self-administration.

Methods: Rats with 1 hour daily cocaine access (short access [ShA]) versus 6-hour access (long access [LgA]) were tested for differences in the effects of the metabotropic glutamate receptor 2/3 (mGluR2/3) agonist (-)-2-oxa-4-aminobicylco(3.1.0)hexane-4,6-dicarboxylic acid (LY379268) and the metabotropic glutamate receptor 5 (mGluR5) antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on cocaine-reinforced progressive-ratio responding and differences in expression levels and functional activity of mGluR2/3 and mGluR5.

Results: The LgA groups showed higher progressive-ratio breakpoints than ShA groups. LY379268 (0-3 mg/kg subcutaneous) dose-dependently lowered breakpoints in the LgA group but reduced breakpoints only at 3 mg/kg in the ShA group. Consistent with this behavioral effect, functional mGluR2/3 activity was significantly elevated following LgA cocaine exposure. MTEP (0-3 mg/kg intraperitoneal) reduced breakpoints in the ShA group only. Long access cocaine exposure was associated with decreased mGluR5 expression, accompanied by reduced functional mGluR5 activity in the nucleus accumbens. A downward trend developed in mGluR5 protein expression in the medial prefrontal cortex and hippocampus.

Conclusions: Functional upregulation of mGluR2/3 and downregulation of mGluR5 are likely factors in the transition to cocaine dependence. The differential behavioral effects of LY379268 and MTEP in rats with a history of long access to cocaine have implications for the treatment target potential of mGluR2/3 and mGluR5.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acids / pharmacology
  • Analysis of Variance
  • Animals
  • Behavior, Addictive / metabolism*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Central Nervous System Depressants / pharmacology*
  • Cocaine / pharmacology*
  • Cocaine-Related Disorders / metabolism*
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / pharmacology
  • Male
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / metabolism*
  • Reinforcement Schedule
  • Self Administration
  • Thiazoles / pharmacology


  • 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine
  • Amino Acids
  • Bridged Bicyclo Compounds, Heterocyclic
  • Central Nervous System Depressants
  • Excitatory Amino Acid Agonists
  • Grm5 protein, rat
  • LY 379268
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor 3
  • Cocaine