Role of protein kinase C epsilon (PKCvarepsilon) in the reduction of ethanol reinforcement due to mGluR5 antagonism in the nucleus accumbens shell.
BACKGROUND
The type 5 metabotropic glutamate receptor (mGluR5) and the epsilon isoform of protein kinase C (PKCepsilon) regulate ethanol intake, and we have previously demonstrated that mGluR5 receptor antagonism reduces ethanol consumption via a PKCepsilon-dependent mechanism.


OBJECTIVE
We explored the potential neuroanatomical substrates of regulation of ethanol reinforcement by this mGluR5-PKCepsilon signaling pathway by infusing selective inhibitors of these proteins into the shell or core region of the nucleus accumbens (NAc).


METHODS
Male Wistar rats were trained to self-administer ethanol intravenously and received intra-NAc infusions of vehicle or the selective mGluR5 antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) alone and in combination with a PKCepsilon translocation inhibitor (epsilonV1-2) or a scrambled control peptide (svarepsilonV1-2). The effects of intra-NAc MTEP on food-reinforced responding and open-field locomotor activity were also determined.


RESULTS
MTEP (1 microg/microl) had no effect on ethanol or food reinforcement or locomotor activity when infused into either region. MTEP (3 microg/microl) reduced ethanol reinforcement when infused into the NAc shell but not the core, and this effect was reversed by epsilonV1-2 (1 microg/microl) but not sepsilonV1-2 (1 microg/microl). In both regions, this concentration of MTEP did not alter food-reinforced responding or locomotor activity, and infusion of epsilonV1-2 alone did not alter ethanol reinforcement. MTEP (10 microg/microl) reduced locomotor activity when infused into the shell; therefore, this concentration was not further tested on responding for ethanol or food.


CONCLUSIONS
Blockade of mGluR5 receptors in the NAc shell reduces ethanol reinforcement via a PKCepsilon-dependent mechanism.
Gass
Justin T
JT
Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President Street, MSC 861, Charleston, SC 29425, USA.
Olive
M Foster
MF
D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D000431:Ethanol / Q000008:administration & dosage*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005247:Feeding Behavior / Q000523:psychology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology
C541428:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)piperidine; D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D010880:Piperidines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D000431:Ethanol; D051744:Protein Kinase C-epsilon