The development of negative emotional states as a result of chronic drug use has a profound impact on substance abuse disorder and has yet to be comprehensively modeled. This award will provide the basis for the refinement of such a model to be used in conjunction with state ofthe art neural electrochemical and electrophysiological measurement techniques to probe the influence of negative affect on drug seeking. The training from the first phase of this award provided the PI a unique skillset and understanding ofthe manner by which drugs of abuse alter and usurp the neural circuitry evolved to process the motivational and hedonic properties of natural rewards.
Specific Aim 1 determined that rapid dopamine release in the nucleus accumbens (NAc) core and shell was differentially altered by rewarding and aversive taste stimuli as well as for a natural reward in situations in which it predicts cocaine versus when it does not. The results of this study have shown that a cocaine-predictive taste cue induces a negative affective state that is linked to increased early-session drug taking. This aversive state appears to be akin to a cue-induced withdrawal state and the results of Specific Aim 2 demonstrated that this negative affective state elevates intracranial self-stimulation (ICSS) reward thresholds, consistent with a conditioned withdrawal state.
Specific Aim 3 will determine if distinct subregions ofthe NAc selectively process associative, versus hedonic aspects ofthe learned aversion to the cocaine-associated cue that promotes drug seeking.
In Specific Aim 4, two experiments will probe the breadtl;) of this phenomenon and the control this negative affective state exerts on drug seeking. The results of these studies will demonstrate whether non-gustatory, drug-predictive cues also elicit a negative affective state that retards extinction responding and promotes relapse. Together these experiments will rigorously test the role of negative affect on drug seeking in rats and allow for a better general understanding of how the environment influences an animal's affect and subsequent behavior.

Public Health Relevance

The findings of these studies will shape our view and treatment of substance abuse disorders. A negative emotional state is associated with drug seeking and relapse in human addicts. The PI will investigate the motivational properties and neural underpinnings of this state that promotes drug seeking. Such investigations could lead to new pharmacotherapies aimed at disrupting the motivation to seek cocaine.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Lynch, Minda
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Marquette University
Other Basic Sciences
Schools of Allied Health Profes
United States
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Hurley, Matthew M; Robble, Mykel R; Callan, Grace et al. (2018) Pituitary adenylate cyclase-activating polypeptide (PACAP) acts in the nucleus accumbens to reduce hedonic drive. Int J Obes (Lond) :
Wheeler, Daniel S; Ebben, Amanda L; Kurtoglu, Beliz et al. (2017) Corticosterone regulates both naturally occurring and cocaine-induced dopamine signaling by selectively decreasing dopamine uptake. Eur J Neurosci 46:2638-2646
Chan, Chung-Lung; Wheeler, Daniel S; Wheeler, Robert A (2016) The neural encoding of cocaine-induced devaluation in the ventral pallidum. Neurobiol Learn Mem 130:177-84
Twining, Robert C; Wheeler, Daniel S; Ebben, Amanda L et al. (2015) Aversive stimuli drive drug seeking in a state of low dopamine tone. Biol Psychiatry 77:895-902
Wheeler, Daniel S; Robble, Mykel A; Hebron, Emily M et al. (2015) Drug predictive cues activate aversion-sensitive striatal neurons that encode drug seeking. J Neurosci 35:7215-25
Freet, Christopher S; Wheeler, Robert A; Leuenberger, Ellen et al. (2013) Fischer rats are more sensitive than Lewis rats to the suppressive effects of morphine and the aversive kappa-opioid agonist spiradoline. Behav Neurosci 127:763-70
Graf, Evan N; Wheeler, Robert A; Baker, David A et al. (2013) Corticosterone acts in the nucleus accumbens to enhance dopamine signaling and potentiate reinstatement of cocaine seeking. J Neurosci 33:11800-10
Park, Jinwoo; Wheeler, Robert A; Fontillas, Khristy et al. (2012) Catecholamines in the bed nucleus of the stria terminalis reciprocally respond to reward and aversion. Biol Psychiatry 71:327-34
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
Jones, J L; Day, J J; Wheeler, R A et al. (2010) The basolateral amygdala differentially regulates conditioned neural responses within the nucleus accumbens core and shell. Neuroscience 169:1186-98

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