Persistent Effects of Self-Administered Cocaine on Cognitive Function and Brain Dopamine Receptors: The Consequences of Differential Drug Access.

Abstract

Drug addicts exhibit a number of cognitive deficits including deficits in frontocortical function and memory that persist long after the discontinuation of drug use. It is not clear, however, whether the cognitive deficits are a consequence of drug use, or are present prior to drug use, and thus are a potential predisposing factor for addiction. Characterizing the ability of drugs of abuse to lead to alterations in cognition and elucidating the molecular mechanisms that underlie these deficits may allow us to develop better treatment regimens for addicts. Animal models provide us with a means to examine the effects of drugs of abuse on cognitive function and underlying dopamine systems however, the usefulness of these models is only as good as they accurately model the human condition. For decades, researchers have utilized relatively limited access self-administration procedures (1-3 hours of daily access) to study addiction. However, more recently, researchers have started utilizing more extended access drug self-administration procedures that provide animals with either months of shorter daily self-administration sessions or longer daily access for 3-4 weeks. These extended access models have allowed experimenters to model the transition to compulsive drug use in animals and provide us with an excellent model with which to study the ability of cocaine to lead to deficits in cognitive function and alterations in ascending dopamine systems. We report that extended access self-administration leads to deficits in both cognitive flexibility and recognition memory performance and these deficits persist during prolonged abstinence. In addition, we report that extended access cocaine self-administration leads to a persistent decrease in dopamine D2 mRNA and protein levels in the prefrontal cortex. In the striatum, we found that cocaine self-administration, both extended and limited access, leads to a persistent increase in the proportion of dopamine D2 high-affinity receptors, while having no effect on total D2 levels. Finally, we determined that extended access cocaine self-administration leads to a biphasic striatal rCBF response, with increases seen during early withdrawal and decreases seen following prolonged withdrawal. This work has important implications for the development of cocaine addiction treatment options, both for pharmacological and cognitive therapies.