Incentive Cocaine-Seeking Habits and Their Compulsive Manifestation Emerge After a Downregulation of the Dopamine Transporter in Astrocytes Across Functional Domains of the Striatum.

The development of compulsive cue-controlled-incentive drug-seeking habits is a hallmark of substance use disorder that 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. This shift is paralleled by drug-induced (including cocaine) 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 occur following cocaine exposure. We compared DAT protein levels in whole tissue homogenates, and in astrocytes cultured from ventral and dorsal striatal territories of drug-naïve 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.