Altered dopamine transmission is implicated in most contemporary theories of drug abuse, but the manner and even the direction of these changes are quite controversial. The most salient behavioral characteristics of the switch from recreational drug use to drug abuse are an increased focus on drug seeking and increased drug consumption. We recently demonstrated that increased drug consumption following chronic use is driven by a decrement in a specific dopamine signal: phasic dopamine release evoked by the response- contingent presentation of drug cues. However, our preliminary data indicate that phasic dopamine release to non-contingent presentation of drug cues (i.e., a potent stimulus for drug seeking and relapse to drug use during abstinence) change in the opposite direction and actually increase with chronic drug use. Collectively, this notion of diametric changes in phasic dopamine release to contingent and non-contingent drug cues, respectively, can resolve apparently contradictory theories of drug addiction. In the proposed work we will test this hypothesis by measuring dopamine release with fast-scan cyclic voltammetry and observing behavior to drug-related cues using different regimens of cocaine self-administration and following periods of drug withdrawal. We will also test whether or not the effect of L-DOPA on restoring dopamine release to contingent presentation of drug cues to reduce drug consumption is mitigated by increasing dopamine release to non-contingent cues and potentially increasing the likelihood of relapse. If not, and L-DOPA selectively increases depleted dopamine release (to contingent cues) without significantly elevating non- depleted dopamine (to contingent cues), we would advocate L-DOPA as a harm-reduction pharmacotherapeutic for reducing drug consumption to provide a window for behavioral and cognitive interventions.
The characteristic traits of substance abuse disorders are increased amount of time spent seeking drugs and increased drug consumption compared to recreational drug users. The proposed work characterizes a pattern of neurochemical changes that increase cue-induced drug seeking and drug consumption following chronic drug use.