The DSM-IV recognizes the emergence of negative affect (e.g., dysphoria, irritability, anhedonia) in addiction, postulated to play a key role in craving and relapse. Prior rewarding experiences (e.g., food, job) become devalued as the addict continues to seek and use drug despite harmful outcomes. Dissecting the neural mechanisms underlying this detrimental consequence of addiction is critical since it may lead to novel treatments that ameliorate negative affective states associated with drug use and decrease the drive for the drug. The nucleus accumbens (NAc) plays a key role in reward processing and NAc neurons encode the critical features of natural and cocaine directed behaviors. Importantly, this processing is highly dynamic and profoundly altered by a variety of factors including drug abstinence. However, understanding the neural basis of natural reward devaluation by cocaine, the development of aversive affect associated with this devaluation, and the potential alteration of this processing by abstinence, has been limited. The Carelli lab began addressing these issues using an animal model developed in the last funding period. NAc activity was examined in rats during intraoral infusion of a sweet taste alone or following devaluation (i.e., when it predicted delayed cocaine availability). Rats exhibited aversive taste reactivity (e.g., gapes) during infusion of the devalued sweet, similar to infusion of quinine, a bitter, aversive tastant. This shift in palatability corresponded to an alteration in NAc activity; cells that previously responded with inhibition during infusion of the sweet shifted to excitatory activity during infusion of the cocaine-devalued tastant. This excitatory response profile is typically observed during quinine infusion, indicating that the once palatable sweet taste becomes aversive following its association with impending cocaine availability, and NAc neurons encode this aversive state. Critically, the expression of this aversion to the sweet taste predicted the subsequent motivation to self- administer cocaine. Likewise, a shift (from increase to decrease) in NAc dopamine (DA) was observed as the aversive state developed. These intriguing findings suggest that cocaine-conditioned cues elicit a cocaine-need state that is aversive, is encoded by a distinct subset of NAc cells and rapid DA signaling, and promotes cocaine seeking. Here, three specific aims are proposed. We will determine the effects of experimenter- controlled cocaine abstinence on NAc cell firing (Aim 1) and rapid DA release (Aim 2) during presentation of a natural reward that predicts delayed cocaine access.
Aim 3 will expand those findings and determine a possible neural mechanism of natural reward devaluation in our model;we will determine if the shift from increased to decreased DA is necessary for the development and/or expression of cocaine-induced negative affect. The proposed studies will provide novel insight into neurobiological mechanisms mediating the emergence negative affective states and the associated devaluation of natural rewards by cocaine, and the effects of abstinence on this phenomenon.

Public Health Relevance

An important feature of cocaine addiction in humans is the emergence of negative affect (e.g., dysphoria, irritability, anhedonia), postulated to play a key role in craving and relapse and exacerbated with prolonged drug abstinence. Indeed, the DSM-IV recognizes that social, occupational and/or recreational activities become reduced as a consequence of repeated drug use whereby previously rewarding experiences (e.g., food, job, family) become devalued as the addict continues to seek and use drug despite negative outcomes. The proposed studies will examine neural mechanisms underlying this detrimental consequence of addiction, and findings generated may aid in the development of novel treatments that ameliorate negative affective states associated with cocaine use and reduce the drive (craving) for the drug.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Volman, Susan
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University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
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Haake, Rachel M; West, Elizabeth A; Wang, Xuefei et al. (2018) Drug-induced dysphoria is enhanced following prolonged cocaine abstinence and dynamically tracked by nucleus accumbens neurons. Addict Biol :
Moschak, Travis M; Wang, Xuefei; Carelli, Regina M (2018) A Neuronal Ensemble in the Rostral Agranular Insula Tracks Cocaine-Induced Devaluation of Natural Reward and Predicts Cocaine Seeking. J Neurosci 38:8463-8472
Moschak, Travis M; Terry, Douglas R; Daughters, Stacey B et al. (2018) Low distress tolerance predicts heightened drug seeking and taking after extended abstinence from cocaine self-administration. Addict Biol 23:130-141
Hurley, Seth W; West, Elizabeth A; Carelli, Regina M (2017) Opposing Roles of Rapid Dopamine Signaling Across the Rostral-Caudal Axis of the Nucleus Accumbens Shell in Drug-Induced Negative Affect. Biol Psychiatry 82:839-846
Cameron, Courtney M; Wightman, R Mark; Carelli, Regina M (2016) One month of cocaine abstinence potentiates rapid dopamine signaling in the nucleus accumbens core. Neuropharmacology 111:223-230
Green, Jennifer L; Dykstra, Linda A; Carelli, Regina M (2015) Examination of cocaine dose in a preclinical model of natural reward devaluation by cocaine. Behav Pharmacol 26:398-402
Carelli, Regina M; West, Elizabeth A (2014) When a good taste turns bad: Neural mechanisms underlying the emergence of negative affect and associated natural reward devaluation by cocaine. Neuropharmacology 76 Pt B:360-9
Cerri, Domenic H; Saddoris, Michael P; Carelli, Regina M (2014) Nucleus accumbens core neurons encode value-independent associations necessary for sensory preconditioning. Behav Neurosci 128:567-578
Saddoris, Michael P; Carelli, Regina M (2014) Cocaine self-administration abolishes associative neural encoding in the nucleus accumbens necessary for higher-order learning. Biol Psychiatry 75:156-64
Sugam, Jonathan A; Saddoris, Michael P; Carelli, Regina M (2014) Nucleus accumbens neurons track behavioral preferences and reward outcomes during risky decision making. Biol Psychiatry 75:807-816

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