Metabotropic glutamate receptor 5 activity in the nucleus accumbens is required for the maintenance of ethanol self-administration in a rat genetic model of high alcohol intake.
BACKGROUND
Systemic modulation of Group I and II metabotropic glutamate receptors (mGluRs) regulate ethanol self-administration in a variety of animal models. Although these receptors are expressed in reward-related brain regions, the anatomical specificity of their functional involvement in ethanol self-administration remains to be characterized. This study sought to evaluate the functional role of Group I (mGluR5) and Group II (mGluR2/3) in mesocorticolimbic brain regions in ethanol self-administration.


METHODS
Alcohol-preferring (P) rats, a genetic model of high alcohol drinking, were trained to self-administer ethanol (15% v/v) versus water in operant conditioning chambers. Effects of brain site-specific infusion of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the mGluR2/3 agonist were then assessed on the maintenance of self-administration.


RESULTS
Microinjection of the mGluR5 antagonist MPEP in the nucleus accumbens reduced ethanol self-administration at a dose that did not alter locomotor activity. By contrast, infusion of the mGluR2/3 agonist LY379268 in the nucleus accumbens reduced self-administration and produced nonspecific reductions in locomotor activity. The mGluR5 involvement showed anatomical specificity as evidenced by lack of effect of MPEP infusion in the dorsomedial caudate or medial prefrontal cortex on ethanol self-administration. To determine reinforcer specificity, P-rats were trained to self-administer sucrose (.4% w/v) versus water, and effects of intra-accumbens MPEP were tested. The MPEP did not alter sucrose self-administration or motor behavior.


CONCLUSIONS
These results suggest that mGluR5 activity specifically in the nucleus accumbens is required for the maintenance of ethanol self-administration in individuals with genetic risk for high alcohol consumption.
Besheer
Joyce
J
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Grondin
Julie J M
JJ
Cannady
Reginald
R
Sharko
Amanda C
AC
Faccidomo
Sara
S
Hodge
Clyde W
CW
D000428:Alcohol Drinking / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D000596:Amino Acids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005518:Food Preferences / Q000187:drug effects; D008297:Male; D008845:Microinjections / Q000379:methods; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012055:Reinforcement Schedule; D012646:Self Administration / Q000379:methods; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002492:Central Nervous System Depressants; D018683:Excitatory Amino Acid Agents; C578937:Grm5 protein, rat; C118218:LY 379268; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013549:Sweetening Agents; D000431:Ethanol; D013395:Sucrose; C121465:6-methyl-2-(phenylethynyl)pyridine