Differential roles of the dorsolateral and midlateral striatum in punished cocaine seeking

Continued instrumental drug seeking despite contingent punishment is a core phenotype of drug addiction. Although the neuroanatomical basis of punished drug seeking is unclear, we hypothesize that the sensorimotor striatum, a structure that mediates habitual drug seeking, also mediates punished cocaine seeking. Forelimb sensorimotor projections into the striatum of the rat extend from the dorsolateral to midlateral striatum. Here, we selectively inactivated the dorsolateral and midlateral striatum in rats responding for cocaine in a seeking-taking task. We inactivated both regions after the acquisition of cocaine seeking, after extended cocaine self-administration and finally after the introduction of intermittent, seeking-contingent foot shock. The results show that inactivation of the dorsolateral striatum selectively disrupted punished drug seeking but did not affect unpunished drug seeking, even after extended training. Inactivation of the midlateral striatum, on the other hand, disrupted drug seeking at all stages of training. The effect of inactivating the dorsolateral striatum under punishment conditions was present before delivery of the first shock in the session, and responding reverted to baseline the next day. Thus, inactivation of the dorsolateral striatum seems to enhance the influence of recalled threat of negative consequences of cocaine seeking. The proportional reduction in responding after inactivation of the dorsolateral striatum did not vary with the individual level of compulsivity. Together, these results suggest a novel differentiation of function in the sensorimotor striatum, where the dorsolateral striatum selectively mediates the rigidity of responding after overtraining, while the midlateral striatum mediates responding itself at all stages of training.