Subsecond dopamine release in the ventral and dorsolateral striatum during the development of compulsive drug taking
Final Report Abstract
Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that with the progression of drug use its control is increasingly dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to establish the spatiotemporal profile of striatal dopamine release and investigate how it changes during the period from initial to compulsive drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling intravenous catheters over the course of three weeks of cocaine self-administration (access for one hour per day; short access, ShA). We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks. This emergent dopamine signaling in DLS mediated discriminated behavior to obtain drug, as shown using intra-DLS infusion of the dopamine antagonist alpha-flupenthixol, but did not promote escalated or compulsive drug use. By applying excitotoxic lesions to the VMS, we also demonstrate that this recruitment of dopamine signaling in the DLS is dependent upon antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responding for cocaine. Therefore, although the predicted anatomical shift in dopamine signaling between VMS and DLS was observed, it manifested itself prior to the emergence of compulsive drug seeking, and rather supported a shift from exploring to exploiting the drug environment. In a follow-up study, we tested how the demonstrated regional dynamics of striatal dopamine signaling observed during stable, established drug use change when access to cocaine is extended from one to six hours per day (long access, LgA), a training regimen commonly used to produce compulsive drug taking. In rats that maintained relatively stable intake across LgA training, phasic dopamine signaling in the VMS following the operant response for drug delivery was present throughout all three weeks of LgA self-administration training. In contrast, in rats that displayed a progressive escalation of drug intake, a corresponding deterioration in VMS dopamine release was observed. Furthermore, escalation of cocaine use was prevented by treating animals with the dopamine precursor L-dopa prior to LgA self-administration sessions and drug intake was reduced in rats that developed escalated drug use after two weeks of LgA by subsequent L-dopa treatment. In contrast to VMS dopamine signaling, DLS signals did not change as a function of drug use. Overall, these findings suggest that dopamine release in the DLS contributes to the development of discriminated, established drug use, whereas the escalation of drug use, a hallmark of addiction, is caused by a depletion of dopamine in the VMS. Thus, contrary to contemporary theoretical considerations and our proposed predictions the crucial factor in the escalation of drug use and presumably in the development of drug addiction is progressively changing dopamine signaling in the VMS, but not the DLS.
