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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.

The rewarding properties of cocaine play a key role in establishing and maintaining the drug-taking habit. However, as exposure to cocaine increases, drug use can transition from controlled to compulsive. Importantly, very little is known about the neurobiological mechanisms that control this switch in drug use that defines addiction. MicroRNAs (miRNAs) are small non-protein coding RNA transcripts that can regulate the expression of messenger RNAs that code for proteins. Because of their highly pleiotropic nature, each miRNA has the potential to regulate hundreds or even thousands of protein-coding RNA transcripts. This property of miRNAs has generated considerable interest in their potential involvement in complex psychiatric disorders such as addiction, as each miRNA could potentially influence the many different molecular and cellular adaptations that arise in response to drug use that are hypothesized to drive the emergence of addiction. Here, we review recent evidence supporting a key role for miRNAs in the ventral striatum in regulating the rewarding and reinforcing properties of cocaine in animals with limited exposure to the drug. Moreover, we discuss evidence suggesting that miRNAs in the dorsal striatum control the escalation of drug intake in rats with extended cocaine access. These findings highlight the central role for miRNAs in drug-induced neuroplasticity in brain reward systems that drive the emergence of compulsive-like drug use in animals, and suggest that a better understanding of how miRNAs control drug intake will provide new insights into the neurobiology of drug addiction.

Compulsive drug seeking, which is characterized by continued instrumental effort despite contingent punishment, has been shown to emerge after extended drug self-administration. Exactly what aspect of drug self-administration drives the appearance of addictive behavior is unclear, but the mechanistic explanations that have been offered differ in one key respect. On one hand, it has been suggested that dysfunctional conditioning during self-administration drives unrealistic reward expectations, ultimately producing resistance to punishment. If this is indeed the pathological process that drives compulsive behavior, then compulsivity should be apparent only in the presence of the pavlovian and instrumental stimuli that underwent frequent pairing with the drug reward. On the other hand, it has also been suggested that extended drug intake produces general changes to reward and decisionmaking circuits that manifest as compulsive drug seeking. Unfortunately, conditioning history and drug intake are generally intrinsically intertwined. However, here we used an animal model of compulsive cocaine seeking to selectively manipulate drug intake and the degree of conditioning in the test context, to investigate which of the two is more important for the emergence of compulsive cocaine seeking. The results show that extended drug intake alone is sufficient, but extended conditioning in the test context is not necessary for the emergence of compulsive cocaine seeking, resolving a fundamental question in addiction research.

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