Regulation of motivation to self-administer ethanol by mGluR5 in alcohol-preferring (P) rats.
BACKGROUND
Emerging evidence indicates that Group I metabotropic glutamate receptors (mGluR1 and mGluR5) differentially regulates ethanol self-administration in several rodent behavioral models. The purpose of this work was to further characterize involvement of Group I mGluRs in the reinforcing effects of ethanol using a progressive ratio schedule of reinforcement.


METHODS
Alcohol-preferring (P) rats were trained to self-administer ethanol (15% v/v) versus water on a concurrent schedule of reinforcement, and the effects of the Group I mGluR antagonists were evaluated on progressive ratio performance. The rats were then trained to self-administer sucrose (0.4% w/v) versus water, and the effects of the antagonists were tested on progressive ratio performance.


RESULTS
The mGluR1 antagonist, 3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl (cis-4-methoxycyclohexyl) methanone (JNJ 16259685; 0 to 1 mg/kg) and the mGluR5 antagonist, 6-methyl-2-(phenylethynyl) pyridine (MPEP; 0 to 10 mg/kg) dose-dependently reduced ethanol break point. In separate locomotor activity assessments, the lowest effective dose of JNJ 16259685 (0.3 mg/kg) produced a motor impairment, whereas the lowest effective dose of MPEP (3 mg/kg) did not. Thus, the reduction in ethanol break point by mGluR1 antagonism was probably a result of a motor impairment. JNJ 16259685 (0.3 mg/kg) and MPEP (10 mg/kg) reduced sucrose break point and produced motor impairments. Thus, the reductions in sucrose break point produced by both Group I antagonists were probably because of nonspecific effects on motor activity.


CONCLUSIONS
Together, these results suggest that glutamate activity at mGluR5 regulates motivation to self-administer ethanol.
Besheer
Joyce
J
Bowles Center for Alcohol Studies, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. jbesheer@med.unc.edu
Faccidomo
Sara
S
Grondin
Julie J M
JJ
Hodge
Clyde W
CW
D000428:Alcohol Drinking / Q000503:physiopathology*; D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D002755:Choice Behavior; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000097:blood / Q000494:pharmacology; D008297:Male; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012055:Reinforcement Schedule
C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D000431:Ethanol