Role of protein kinase C epsilon (PKCε) 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 (PKCε) regulate ethanol intake, and we have previously demonstrated that mGluR5 receptor antagonism reduces ethanol consumption via a PKCε-dependent mechanism. Objectives: We explored the potential neuroanatomical substrates of regulation of ethanol reinforcement by this mGluR5-PKCε 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 PKCε translocation inhibitor (εV1-2) or a scrambled control peptide (sεV1-2). The effects of intra-NAc MTEP on food-reinforced responding and open-field locomotor activity were also determined. Results: MTEP (1 μg/μl) had no effect on ethanol or food reinforcement or locomotor activity when infused into either region. MTEP (3 μg/μl) reduced ethanol reinforcement when infused into the NAc shell but not the core, and this effect was reversed by εV1-2 (1 μg/μl) but not sεV1-2 (1 μg/μl). In both regions, this concentration of MTEP did not alter food-reinforced responding or locomotor activity, and infusion of εV1-2 alone did not alter ethanol reinforcement. MTEP (10 μg/μl) 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 PKCε-dependent mechanism.