Effects of Cholinergic Interneuron Inhibition in the Nucleus Accumbens during Rodent Drug Reinstatement

Abstract

A variety of previous studies have demonstrated that the nucleus accumbens, a region located in the basal forebrain, holds a critical role in various forms of learning, especially reward and drug-related learning. In the nucleus accumbens, there exists an extremely sparse population of cholinergic interneurons that have been shown to exert powerful control over the output of the entire region during different forms of drug learning, particularly with cocaine. Although these cholinergic interneurons seem to play a large role in the circuitry of the nucleus accumbens during cocaine learning, their specific function is not yet well understood. They have previously been shown to have influence over the formation of a cocaine-context association, as well as its subsequent extinction, but the question still remains about whether they exert the same influence over the reinstatement of an extinguished drug-context association. In this study, we sought to address this question directly by optogenetically inhibiting the cholinergic interneurons during a drug-induced reinstatement of a drug-context association in experimental mice during a cocaine conditioned place preference (cCPP) task, and observing the effects of the inhibition of rodent behavior when compared to control mice. Although we initially thought, based on previous research, that the activity of these interneurons would be necessary for a reinstatement to successfully occur, we ultimately found no evidence that the silencing of the interneurons had any effect on the reinstatement. Both groups of mice successfully reinstated their previously extinguished drug-context association. Since converging evidence supports the success of our optogenetic inhibition, we concluded that the cholinergic interneurons are not necessary for a drug reinstatement. Possible interpretations of this result, limitations of our current study, and future directions based directly on this work are also discussed.