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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA014339-12A1
Application #
8628486
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2001-07-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
12
Fiscal Year
2014
Total Cost
$334,446
Indirect Cost
$109,446
Name
University of North Carolina Chapel Hill
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Cerri, Domenic H; Saddoris, Michael P; Carelli, Regina M (2014) Nucleus accumbens core neurons encode value-independent associations necessary for sensory preconditioning. Behav Neurosci 128:567-78
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
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
West, Elizabeth A; Saddoris, Michael P; Kerfoot, Erin C et al. (2014) Prelimbic and infralimbic cortical regions differentially encode cocaine-associated stimuli and cocaine-seeking before and following abstinence. Eur J Neurosci 39:1891-902
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 75:807-16
Sugam, Jonathan A; Carelli, Regina M (2013) Rolling the dice: the importance of mesolimbic dopamine signaling in risky decision making. Neuropsychopharmacology 38:248
Cameron, Courtney M; Carelli, Regina M (2012) Cocaine abstinence alters nucleus accumbens firing dynamics during goal-directed behaviors for cocaine and sucrose. Eur J Neurosci 35:940-51
Wheeler, Robert A; Aragona, Brandon J; Fuhrmann, Katherine A et al. (2011) Cocaine cues drive opposing context-dependent shifts in reward processing and emotional state. Biol Psychiatry 69:1067-74
Day, Jeremy J; Jones, Joshua L; Carelli, Regina M (2011) Nucleus accumbens neurons encode predicted and ongoing reward costs in rats. Eur J Neurosci 33:308-21
Saddoris, Michael P; Stamatakis, Alice; Carelli, Regina M (2011) Neural correlates of Pavlovian-to-instrumental transfer in the nucleus accumbens shell are selectively potentiated following cocaine self-administration. Eur J Neurosci 33:2274-87

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