Drug addiction is characterized by cycles of compulsive drug use followed by periods of abstinence and relapse. Cues associated with prior drug use elicits drug craving that is highly associated with drug relapse. Addicted individuals are also more likely to exhibit changes in behavior in nondrug situations, such as increased risk taking and impulsiveness, and decreased motivation toward effortful activities. These findings suggest that chronic drug use induces persistent changes in the neural circuits that normally process associative learning and motivated behavior more generally. The ability of stimuli to subsequently elicit approach behavior has largely been attributed to dopamine signaling in the nucleus accumbens. This proposal will open a new avenue of exploration by providing unprecedented analysis of rapid, transient adenosine signaling in the nucleus accumbens by studying adenosine release kinetics in cocaine-nave and cocaine- experienced animals. Adenosine is known to produce a multitude of functions in the brain that have largely been attributed to the basal tone of intra- and extracellular adenosine. Our current knowledge of adenosine signaling in the mesolimbic circuit is derived from studies largely examining adenosine receptor functions using genetic models and pharmacological agents. Phasic adenosine release, however, is a poorly understood phenomenon largely due to the challenges associated with measuring adenosine release with sufficient sensitivity and spatiotemporal resolution. Our preliminary findings demonstrate that fast-scan cyclic voltammetry can be used successfully in awake, behaving animals to measure phasic adenosine release under naturalistic learning conditions. The studies in Aim 1 will characterize adenosine signaling kinetics in the nucleus accumbens in cocaine-nave and cocaine-experienced rats. These studies are expected to provide novel data illustrating that prior cocaine experience disrupts phasic adenosine signaling kinetics in the nucleus accumbens and produces differential sensitivity on adenosine signaling in response to the adenosine antagonist caffeine. The studies in Aim 2 will evaluate the role of adenosine neurotransmission in the nucleus accumbens during a Pavlovian discrimination task. These studies are expected to provide novel data illustrating that 1) adenosine signaling is rapid (sub-second) and tracks behaviorally-relevant events in real time, 2) adenosine and dopamine co-transmission is temporally coordinated to encode distinct aspects of Pavlovian associations, and 3) that cocaine experience alters both the phasic release of adenosine and disrupts the functional balance in adenosine and DA signaling in the nucleus accumbens that is necessary for learning. Together, the proposed studies will significantly advance our understanding of adenosine signaling in the nucleus accumbens for both drug addiction and naturalistic learning.
PUBLIC HEALTH RELEVANCE: Drug addiction is a serious mental illness that involves significant motivational disturbances resulting in a loss of behavioral control leading to destruction of the afflicted individual as well as their surrounding social networks. This disease affects millions of people and generates enormous social and economic costs to society. The goal of this research is to better understand how cocaine intake disrupts adenosine signaling and relates to learning.
