Terminal dopamine release kinetics in the accumbens core and shell are distinctly altered following withdrawal from cocaine self-administration

Abstract

Repeated self-administration of cocaine is associated with impairments in motivated behaviors as well as alterations in both dopamine (DA) release and neural signaling within the nucleus accumbens (NAc). These impairments are present even after several weeks of abstinence from drug taking, suggesting that the self-administration experience induces long-lasting neuroplastic alterations in the mesolimbic DA circuit. To understand these changes at the terminal level, rats were allowed to self-administer either cocaine intravenously (∼1 mg/kg per infusion; Cocaine) or water to a receptacle (Control) in 2-hour sessions over 14 days, followed by 30 days of enforced abstinence. Fast-scan cyclic voltammetry was then used to record real-time DA release in either the NAc core or shell following electrical stimulations of the ventral tegmental area (VTA) in freely-moving animals. In Controls, the kinetics of DA release in the core and shell strikingly differed, with shell displaying slower release and reuptake rates than core. However, cocaine experience differentially altered these signaling patterns by NAc subregion. In the shell, Cocaine rats showed less sensitivity to the dynamic range of applied stimulations than Controls. In the core, by contrast, Cocaine rats displayed robustly reduced peak DA release given the same stimulation, while also showing slower release and reuptake kinetics. The differential effects of cocaine self-administration on terminal function between core and shell is consistent with a region-specific functional reorganization of the mesolimbic DA system following repeated, and may provide an anatomical substrate for altered cognitive function following chronic drug-taking and addiction.

Significance Statement: Chronic drug use alters neural signaling (particularly dopamine), even after extended periods of drug abstinence. Evidence suggests that dopamine terminals may be persistently altered in cocaine-experienced animals, (i.e., influencing the rates and amount of dopamine release and reuptake) but it is not known whether this is a general property of the dopamine system, or if instead, changes are unique within different terminal regions. Voltammetric recordings in the nucleus accumbens core and shell in cocaine-experienced rats revealed region-specific differences in release/reuptake kinetics relative to controls. Strikingly, while drug-naïve subjects showed consistent differences in dopamine kinetics between core and shell, cocaine remodeled the entire accumbens to become more “shell-like”. Understanding this remodeling will be critical for developing treatments to prevent drug relapse.