Several studies have examined the effects of mGlu5 antagonists on operant ethanol self-administration behaviors in P rats as well. Systemic administration of the mGlu5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) can reduce operant ethanol self-administration,134 reduce ethanol breakpoint without affecting sucrose breakpoint or locomotor activity,135 and block the repeated alcohol-deprivation effect (ADE).134 The effects of MPEP in rats were extended to mice by demonstrating that this mGlu5 antagonist interfered with the acquisition and maintenance of ethanol drinking by C57BL/6J mice as well,136,137 which appears to depend upon a protein kinase C-epsilon (PKC-epsilon) pathway.138 A subsequent study using P rats139 examined the effects of systemic MPEP on the extracellular signal-regulated kinase (ERK1/2) pathway,140 which is downstream of mGlu5 and implicated in addiction. MPEP attenuated cue-induced reinstatement of ethanol-seeking behavior, which was associated with decreased phosphorylated (p)ERK1/2 immunoreactivity (IR) in the BLA, but not CeA, and AcbSh, but not AcbCo.139 These findings support a role for ERK1/2 phosphorylation in the BLA and AcbSh in mediating cue-induced reinstatement of ethanol-seeking behavior. A third study from this laboratory141 confirmed a role for mGlu5 within the AcbCo in
