Compulsion derived from incentive cocaine-seeking habits is associated with a downregulation of the dopamine transporter in striatal astrocytes

Abstract

The development of compulsive cue-controlled -incentive- drug-seeking habits, a hallmark of substance use disorder, is predicated on an intrastriatal shift in the locus of control over behaviour from a nucleus accumbens (Nac) core - dorsomedial striatum network to a Nac core - anterior dorsolateral striatum (aDLS) network. Such shift parallels striatal adaptations to chronic drug, including cocaine self-administration, marked by dopamine transporter (DAT) alterations originating in the ventral striatum that spread eventually to encompass the aDLS. Having recently shown that heroin self-administration results in a pan-striatal reduction in astrocytic DAT that precedes the development of aDLS dopamine-dependent incentive heroin-seeking habits we tested the hypothesis that similar adaptations occurr following cocaine exposure. We compared DAT protein levels in whole tissue homogenates, and astrocytes cultured from ventral and dorsal striatal territories of drug naive male Sprague Dawley rats to those of rats with a history of cocaine-taking or an aDLS dopamine-dependent incentive cocaine-seeking habit. Cocaine exposure resulted in a decrease in whole tissue and astrocytic DAT across all territories of the striatum. We further demonstrated that compulsive, i.e., punishment-resistant, incentive cocaine-seeking habits were associated with a reduction in DAT mRNA levels in the Nac shell, but not the Nac core-aDLS incentive habit system. Together with the recent evidence of heroin-induced downregulation of striatal astrocytic DAT, these findings suggest that alterations in astrocytic DAT may represent a common mechanism underlying the development of compulsive incentive drug-seeking habits across drug classes.