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.
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.
Hao
Yue
Y
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California, USA. yuehao@scripps.edu
Martin-Fardon
Rémi
R
Weiss
Friedbert
F
D000596:Amino Acids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D012055:Reinforcement Schedule; D012646:Self Administration; D013844:Thiazoles / Q000494:pharmacology
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002492:Central Nervous System Depressants; D018690:Excitatory Amino Acid Agonists; C578937:Grm5 protein, rat; C118218:LY 379268; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D003042:Cocaine