Circadian Rhythms and Cocaine Use Disorder

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PROJECT SUMMARY Despite decades of critical research into its biological mechanisms and treatment approaches, Substance Use Disorder (SUD) persists as a major world health problem. In the last few years, approximately 21 million people required SUD treatment. Still, recent years have seen dramatic increases in the number of overdose deaths due to heroin, prescription opioids, and cocaine. Interestingly, there is some work that suggests a circadian rhythm and robust time-of-day shifts in the function of specific receptors and neurotransmitter systems that are routinely implicated in drug abuse vulnerability and relapse. For example, diurnal (i.e., light/dark) variation has been observed in mesolimbic dopamine (DA) system, including rhythms in extracellular DA tone, DA transporter levels/ function, and DA receptor function. Moreover, research in both humans and animal models has observed that level of drug taking and seeking can vary throughout the day. While published work demonstrates regulators of diurnal variation in DA tone and tone regulators, there is a large gap in research dedicated to understanding regulators of diurnal variation and circadian rhythms in subsecond, phasic DA release. This is particularly important given the role of phasic DA release in reinforcement learning, motivation, and goal-directed behavior that is altered in SUD. Moreover, little work has been dedicated to understanding how the function of intrinsic modulators of phasic DA release, such as acetylcholine (ACh) from striatal cholinergic interneurons, vary across time-of-day. Therefore, the overall objective of this research proposal is to determine the circadian diurnal differences in rapid DA and ACh signaling and how these rhythms are mechanistically linked to changes in motivated behavior, cocaine/reward seeking, and cue-reward associations. Our central hypothesis is that there are times-of-day that individuals will exhibit increased sensitivity to reward- and cocaine-associated cues that can lead to cocaine seeking, which are mediated by time-of-day variations in the cholinergic interneuron modulation of rapid DA signaling. Specific Aim 1 will use rat models to investigate diurnal variation in 1) incentive motivational value towards reward-associated cues using pavlovian conditioned approach task, 2) the degree to which cues increase instrumental responding using a pavlovian-instrumental transfer task, and 3) the subjective value of cocaine and corresponding motivation to take cocaine. We will also examine the magnitude of both DA and ACh signaling in the nucleus accumbens (NAc) core using ex vivo fast scan cyclic voltammetry across the light / dark cycles. Specific Aims 2 and 3 will utilize voltammetry, fiber photometry, and optogenetics in freely- behaving rats to measure diurnal modulation of phasic DA and CIN activity across a 24-hour day and define a circuit specific mechanism for differences in motivated behavior, cocaine seeking, and corresponding magnitude of NAc DA signals across the light and dark cycle.