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

Excessive cocaine use results from decreased phasic dopamine signaling in the striatum

Drug addiction is a neuropsychiatric disorder marked by escalating drug use. Dopamine neurotransmission in the ventromedial striatum (VMS) mediates acute reinforcing effects of abused drugs, but with protracted use the dorsolateral striatum is thought to assume control over drug seeking. We measured striatal dopamine release during a cocaine self-administration regimen that produced escalation of drug taking in rats. Surprisingly, we found that phasic dopamine decreased in both regions as the rate of cocaine intake increased, with the decrement in dopamine in the VMS significantly correlated with the rate of escalation. Administration of the dopamine precursor L-DOPA at a dose that replenished dopamine signaling in the VMS reversed escalation, thereby demonstrating a causal relationship between diminished dopamine transmission and excessive drug use. Together these data provide mechanistic and therapeutic insight into the excessive drug intake that emerges following protracted use

Genetic Isolation of Hypothalamic Neurons that Regulate Context-Specific Male Social Behavior.

Nearly all animals engage in a complex assortment of social behaviors that are essential for the survival of the species. In mammals, these behaviors are regulated by sub-nuclei within the hypothalamus, but the specific cell types within these nuclei responsible for coordinating behavior in distinct contexts are only beginning to be resolved. Here, we identify a population of neurons in the ventral premammillary nucleus of the hypothalamus (PMV) that are strongly activated in male intruder mice in response to a larger resident male but that are not responsive to females. Using a combination of molecular and genetic approaches, we demonstrate that these PMV neurons regulate intruder-specific male social behavior and social novelty recognition in a manner dependent on synaptic release of the excitatory neurotransmitter glutamate. These data provide direct evidence for a unique population of neurons that regulate social behaviors in specific contexts

Time-dependent assessment of stimulus-evoked regional dopamine release

To date, the spatiotemporal release of specific neurotransmitters at physiological levels in the human brain cannot be detected. Here, we present a method that relates minute-by-minute fluctuations of the positron emission tomography (PET) radioligand [11C]raclopride directly to subsecond dopamine release events. We show theoretically that synaptic dopamine release induces low frequency temporal variations of extrasynaptic extracellular dopamine levels, at time scales of one minute, that can evoke detectable temporal variations in the [11C] raclopride signal. Hence, dopaminergic activity can be monitored via temporal fluctuations in the [11C] raclopride PET signal. We validate this theory using fast-scan cyclic voltammetry and [11C] raclopride PET in mice during chemogenetic activation of dopaminergic neurons. We then apply the method to data from human subjects given a palatable milkshake and discover immediate and-for the first time-delayed food-induced dopamine release. This method enables time-dependent regional monitoring of stimulus-evoked dopamine release at physiological levels

Pramipexole enhances disadvantageous decision-making: Lack of relation to changes in phasic dopamine release

Pramipexole (PPX) is a high-affinity D2-like dopamine receptor agonist, used in the treatment of Parkinson's disease (PD) and restless leg syndrome. Recent evidence indicates that PPX increases the risk of problem gambling and impulse-control disorders in vulnerable patients. Although the molecular bases of these complications remain unclear, several authors have theorized that PPX may increase risk propensity by activating presynaptic dopamine receptors in the mesolimbic system, resulting in the reduction of dopamine release in the nucleus accumbens (NAcc). To test this possibility, we subjected rats to a probability-discounting task specifically designed to capture the response to disadvantageous options. PPX enhanced disadvantageous decision-making at a dose (0.3 mg/kg/day, SC) that reduced phasic dopamine release in the NAcc. To test whether these modifications in dopamine efflux were responsible for the observed neuroeconomic deficits, PPX was administered in combination with the monoamine-depleting agent reserpine (RES), at a low dose (1 mg/kg/day, SC) that did not affect baseline locomotor and operant responses. Contrary to our predictions, RES surprisingly exacerbated the effects of PPX on disadvantageous decision-making, even though it failed to augment PPX-induced decreases in phasic dopamine release. These results collectively suggest that PPX impairs the discounting of probabilistic losses and that the enhancement in risk-taking behaviors secondary to this drug may be dissociated from dynamic changes in mesolimbic dopamine release