Cue-induced reinstatement of seeking behavior in male rats is independent from the rewarding value of the primary reinforcer: Effect of mGluR5 blockade

Abstract

Environmental conditioning factors have a profound impact on alcohol-seeking behavior and the maintenance of alcohol use in individuals with alcohol dependence. Cues associated with alcohol, depending on the perceived value of the primary reinforcer, gain salience and can trigger relapse.This study investigates the correlation between the reward magnitude of the primary reinforcer and the reinstatement evoked by cues predictive of their availability in male rats. Rat self-administration procedures were used to test reinstatement, with reinforcers consisting of 10% alcohol, 10% sucrose, or 2% sodium chloride (NaCl) experienced under need-state conditions. The effect of MTEP ([(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine), a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, on motivation and reinstatement behaviors was also evaluated. Resultsdemonstrate that under Fixed Ratio 1 (FR1) schedule, the three reinforcers maintain operant responding with the following order of magnitude 10% sucrose >2% NaCl >10% alcohol > water. Under a progressive ratio (PR) schedule of reinforcement, rats exhibit a significantly higher breakpoint for 2% NaCl (under Na-depletion), followed by 10% sucrose and 10% alcohol. After extinction, a significant reinstatement is observed with the magnitude order of 10% sucrose >10% alcohol >2% NaCl. However, only re-exposure to alcohol-paired cues induced significant reinstatement of alcohol-seeking after 4 and 8 months. Treatment with MTEP significantly reduces reinstatement of responding across all reinforcers, with the strongest effect observed on alcohol-seeking. These findings suggest that mGluR5 plays a general role in controlling cue-reactivity, but the effect is prominent in the case of alcohol compared to natural rewards.In conclusion, the results demonstrate a remarkable dissociation between the rewarding magnitude of the primary reinforcer and its ability to trigger relapse upon presentation of a cue previously associated with it. Importantly, alcohol, despite having lower intrinsic motivational value compared to a natural reward (sucrose) or a consummatory stimulus experienced under need state conditions (NaCl), can elicit more robust and longer-term reinstatement of seeking responses. Finally, our data demonstrate a significant involvement of the mGluR5 system in the regulation of seeking behavior.