Differential reductions in alcohol consumption and cue-induced alcohol-seeking behavior following mGlu5 receptor inhibition in the prelimbic vs. infralimbic subregions of the rat prefrontal cortex.

Glutamatergic signaling is one of the primary targets of actions of alcohol in the brain, and dysregulated excitatory transmission in the prefrontal cortex (PFC) may contribute problematic drinking and relapse. A prominent component of glutamate signaling is the type 5 metabotropic glutamate (mGlu5) receptor. However, little is known about the role of this receptor type in subregions of the PFC that regulate either alcohol intake or alcohol-seeking behavior. Here we examined the effects of microinfusions of the selective mGlu5 inhibitor 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) into either the prelimbic (PL) or infralimbic (IL) regions of the PFC on alcohol intake or cue-evoked reinstatement of alcohol-seeking behavior. Adult male Wistar rats were trained to self-administer 10 % alcohol in the presence of compound discriminative stimuli (SD) signaling alcohol availability (S+) or non-availability (S-). In one group of animals, effects of locally administered MTEP (0, 0.5 or 1 μg/μl) into either the PL or IL on active alcohol intake were examined. MTEP was without effect on alcohol self-administration when infused into the PL, but decreased alcohol intake at both doses tested when infused into the IL. In separate groups of animals, we examined effects of locally administered MTEP (0, 0.5 or 1 μg/μl) into either the PL or IL on reinstatement of alcohol seeking elicited by alcohol predictive stimuli (S+). When infused into the PL, MTEP attenuated cue-induced reinstatement only at the higher dose tested (1 μg/μl), but when infused into the IL, MTEP reduced cue-induced reinstatement at both doses tested (0.5 μg/μl and 1 μg/μl). Together, these results suggest a largely preferential role for mGlu5 signaling in the IL vs. PL in regulating both alcohol self-administration behavior and cue-elicited alcohol seeking. Neuromodulatory approaches aimed at reducing mGlu5 signaling in the IL may therefore be of potential therapeutic value in problematic alcohol use.