Role of protein kinase C epsilon (PKCvarepsilon) in the reduction of ethanol reinforcement due to mGluR5 antagonism in the nucleus accumbens shell.

Rationale: 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.

Objectives: 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.