Diametric Changes in Ventral Striatal Dopamine Release Regulate Drug-Taking and Drug-Seeking Behavior

Thesis (Ph.D.)--University of Washington, 2017-03The overall goal of this dissertation work was to determine how drug-cue elicited phasic dopamine neurotransmission changes over prolonged drug use, in both drug-taking and drug-seeking contexts. My initial work, done in collaboration with Dr. Ingo Willuhn, illustrated differences in dopamine dynamics between striatal subregions during active drug taking periods, and demonstrated a causal role for ventral striatal cue-elicited dopamine signals in regulating drug intake. Through these studies, we found that decreases in ventral striatal phasic dopamine release evoked by drug cues drive the escalation of drug intake observed in rats given protracted drug access (Chapter 2). These results are consistent with one of the preeminent theories of drug abuse, which implicates ventral striatal dopamine in producing drug satiety and regulating drug taking behavior. Though altered dopamine transmission is implicated in most contemporary theories of drug abuse, the timing, context, and directionality of these changes remain a matter of debate. In contrast to the satiety theory, another large body of work suggests that ventral striatal dopamine mediates craving and promotes cue driven drug-seeking. Do these theoretical changes in dopamine actually co-exist? This is the question that has driven the bulk of my dissertation work. Drug cues serve different purposes in different situations. During drug taking, cues confirm the success of drug seeking actions and indicate imminent drug delivery, signaling that drug seeking can be terminated. In contrast, during reinstatement paradigms, the same cues, presented unexpectedly during abstinence, signal possible drug availability nearby and promote initiation of drug seeking. The objective of my work was to understand how the dynamics of ventral striatal phasic dopamine signals, evoked by drug cues that are presented unexpectedly during abstinence, differ from those observed during drug taking. To study this, I used fast-scan cyclic voltammetry, an electrochemical detection method that allows for real time monitoring of dopamine release in situ, in awake behaving animals, to measure cue-elicited phasic dopamine signals throughout cocaine self-administration and following long periods of abstinence. The main findings are summarized below: Unexpected drug cues elicit larger dopamine responses over drug taking history. I found that over the course of drug history, the directionality of changes in cue elicited signals obtained in drug-taking and drug-seeking contexts oppose one another. Specifically, cue elicited signals during drug-taking decrease over time, whereas, at the same time point unexpected presentation of the same cues in a drug seeking context produces larger dopamine signals over time (Chapter 3). Dopamine responses elicited by unexpected drug cues increase during abstinence. Studies by Grimm et al. (2001), and others, have demonstrated a positive correlation between the duration of abstinence, and resistance to extinguish responding for drug cues, a phenomenon that has been termed the “incubation of craving”. We hypothesized that this resistance to extinction after prolonged abstinence was mediated by an increase in cue elicited dopamine release. I measured unexpected cue elicited phasic dopamine release after one day or one month of abstinence and observed striking increases in dopamine release evoked by cues after longer periods of abstinence (Chapter 4). These increases in dopamine paralleled the incubation of craving, and increases in cue elicited drug seeking as assessed by conditioned approach behavior. These data are consistent with ventral striatal dopamine mediating craving and promoting drug seeking, an idea with empirical support from many previous studies. Collectively, these studies suggest that the dynamics of cue elicited phasic dopamine transmission depend upon the context in which cues are presented, and explain how dopamine in the ventral striatum might contribute to different, but equally important, core symptoms of substance use disorders