Incentive and Dopamine Sensitization Produced by Intermittent but Not Long Access Cocaine Self-Administration

ABSTRACT Recent studies suggest that the temporal pattern of drug use (pharmacokinetics) has a profound effect on the ability of self-administered cocaine to produce addiction-like behavior in rodents, and to change the brain. To further address this issue, we compared the effects of Long Access (LgA) cocaine self-administration, which is widely used to model the transition to addiction, with Intermittent Access (IntA), which is thought to better reflect the pattern of drug use in humans, on the ability of self-administered cocaine to increase dopamine (DA) overflow in the core of the nucleus accumbens (using in vivo microdialysis), and to produce addiction-like behavior. IntA experience was more effective than LgA in producing addiction-like behavior – a drug experience-dependent increase in motivation for cocaine assessed using behavioral economic procedures, and cue-induced reinstatement – despite much less total drug consumption. There were no group differences in basal levels of DA in dialysate, but a single self-administered IV injection of cocaine increased DA in the core of the nucleus accumbens to a greater extent in rats with prior IntA experience than those with LgA or Short Access (ShA) experience, and the latter two groups did not differ. Furthermore, high motivation for cocaine was associated with a high DA response. Thus, IntA, but not LgA, produced both incentive and DA sensitization. This is consistent with the notion that a hyper-responsive dopaminergic system may contribute to the transition from casual patterns of drug use to the problematic patterns that define addiction.