Dynamics of dopamine release in the striatum and its alterations with psychiatric pathology

Abstract

Altered dopamine transmission is implicated in any contemporary theories of substance abuse. However, the direction, timing, and context in which alterations of dopamine transmission occur remain a matter of debate. Both drugs themselves, and the cues that have been repeatedly paired with drugs are capable of driving dopamine release in the nucleus accumbens core.

In the current work, we observe paradoxical changes in drug-cue elicited dopamine transmission in mediating the escalation of drug intake and resumption of drug-seeking following abstinence, two important hallmarks of addiction. Specifically, attenuation of phasic dopamine transmission to response-contingent drug cues was observed in animals that escalated their daily drug consumption. Additionally, increasing dopamine release by administering levodopa, a dopamine precursor, prevents or reverses escalation of drug-intake. In opposition, phasic dopamine transmission increased across training within the nucleus accumbens core in response to non-contingent drug-associated cues, which coincided with an increase in drug-seeking behaviors. Furthermore, the increase in phasic dopamine transmission to non-contingent drug-cues was further enhanced during withdrawal periods.

Due to this divergence of phasic dopamine transmission observed in response to drug-related cues, we hypothesized that phasic dopamine transmission in the nucleus accumbens core is mediates escalation of drug-taking, and drug-seeking in a divergent manner. Indeed, using optogenetic phasic stimulation of dopamine terminals in the nucleus accumbens core, we observed reversal of escalation of drug consumption (i.e. reduced drug taking) when the stimulation was delivered coincident with the presentation of response-contingent drug cues. However, if the same stimulation was delivered during the non-contingent presentation of a drug cue, the result was increase drug seeking. These results demonstrate that the action of phasic dopamine in the nucleus accumbens on drug-related because is dependent upon the context in which the dopamine is released. Dopamine reduces drug seeking when it is released as a result of a successful action to obtain drug. However, dopamine increases drug seeking when it is released during the presentation of a drug cue that was not the result of the subject's actions. Moreover, during a chronic history of substance use, dopamine signals that reduce drug seeking diminish and that enhance drug seeking increase.