Effects of the mGlu2/3 agonist LY379268 and the mGlu5 antagonist MTEP on ethanol seeking and reinforcement are differentially altered in rats with a history of ethanol dependence.
BACKGROUND
Growing evidence supports a role of metabotropic glutamate receptors (mGluRs) in ethanol reinforcement, ethanol seeking, and ethanol withdrawal. To extend the understanding of the role of mGluRs in the addiction-relevant effects of ethanol as well as of the treatment target potential of these receptors for alcohol abuse, the effects of a selective mGlu2/3 agonist (LY379268) and a selective mGlu5 antagonist (MTEP) were tested on two processes central to alcohol addiction: ethanol reinforcement and stress-induced reinstatement of ethanol seeking in rats with a history of ethanol dependence.


METHODS
Following operant ethanol self-administration training, male Wistar rats were made dependent by intragastric ethanol intubations. Ethanol dependence was confirmed by the presence of somatic withdrawal signs. Following 2 weeks of withdrawal, stable ethanol self-administration was reestablished, and the effects of LY379268 (0-3 mg/kg subcutaneous) and MTEP (0-3 mg/kg, intraperitoneal) on ethanol self-administration were determined in both nondependent and postdependent rats. A second set of rats underwent extinction training and then was tested for the effects of LY379268 or MTEP on reinstatement of ethanol seeking induced by footshock stress.


RESULTS
LY379268 and MTEP dose-dependently reduced both ethanol self-administration and reinstatement of ethanol seeking induced by footshock stress. Additionally, LY379268 was more effective than MTEP in inhibiting both behaviors in postdependent than in nondependent animals.


CONCLUSIONS
These findings suggest that neuroadaptation associated with chronic ethanol exposure or withdrawal alters the sensitivity of mGlu2/3 receptors, with implications for the understanding of the neural basis of alcohol dependence and the treatment target potential of these receptors.
Sidhpura
Nimish
N
The Scripps Research Institute, Molecular and Integrative Neurosciences Department, La Jolla, California 92037, USA. nsidhp@scripps.edu
Weiss
Friedbert
F
Martin-Fardon
Rémi
R
D000437:Alcoholism / Q000097:blood / Q000517:prevention & control* / Q000523:psychology; D000596:Amino Acids / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood; D018683:Excitatory Amino Acid Agents / Q000008:administration & dosage*; D008297:Male; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000379:methods; D013315:Stress, Psychological / Q000503:physiopathology; D013844:Thiazoles / Q000008:administration & dosage*
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018683:Excitatory Amino Acid Agents; C118218:LY 379268; D011725:Pyridines; D013844:Thiazoles; D000431:Ethanol