Compulsive Alcohol Seeking Results from a Failure to Disengage Dorsolateral Striatal Control over Behavior

摘要

The acquisition of drug, including alcohol, use is associated with activation of the mesolimbic dopamine system. However, over the course of drug exposure the control over drug seeking progressively devolves to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms. The causal importance of this functional recruitment of aDLS in the switch from controlled to compulsive drug use in vulnerable individuals remains to be established. Here we tested the hypothesis that individual differences in the susceptibility to aDLS dopamine-dependent control over alcohol seeking predicts and underlies the development of compulsive alcohol seeking. Male alcohol-preferring rats, the alcohol-preferring phenotype of which was confirmed in an intermittent two-bottle choice procedure, were implanted bilaterally with cannulae above the aDLS and trained instrumentally on a seeking–taking chained schedule of alcohol reinforcement until some individuals developed compulsive seeking behavior. The susceptibility to aDLS dopamine control over behavior was investigated before and after the development of compulsivity by measuring the extent to which bilateral aDLS infusions of the dopamine receptor antagonist α-flupenthixol (0, 5, 10, and 15 μg/side) decreased alcohol seeking at different stages of training, as follows: (1) after acquisition of instrumental taking responses for alcohol; (2) after alcohol-seeking behavior was well established; and (3) after the development of punishment-resistant alcohol seeking. Only alcohol-seeking, not alcohol-taking, responses became dependent on aDLS dopamine. Further, marked individual differences in the susceptibility of alcohol seeking to aDLS dopamine receptor blockade actually predicted the vulnerability to develop compulsive alcohol seeking, but only in subjects dependent on aDLS dopamine-dependent control.>SIGNIFICANCE STATEMENT Over the course of addictive drug exposure, there is a transition in the control over drug seeking from ventral to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms, but it is unclear whether this is causally involved in the development of compulsive drug seeking. We tested the hypothesis that individual differences in the reliance of alcohol seeking on aDLS dopamine predicts and underlies the emergence of compulsive alcohol seeking. We identified individual differences in the reliance of well established alcohol seeking, but not taking behavior, on aDLS mechanisms and also showed that this predicted the subsequent development of compulsive alcohol-seeking behavior. Thus, those individuals in whom alcohol seeking depended on aDLS mechanisms were vulnerable subsequently to display compulsivity.