Cocaine dependence is a chronic condition because of the high incidence of relapse that occurs even after prolonged periods of abstinence. Thus, successful treatment must include relapse prevention. The objective of this grant is to elucidate the neural mechanisms underlying incentive motivational effects produced by sampling cocaine or by exposure to cocaine-associated cues (e.g., paraphernalia, cocaine- taking environment, etc), both of which are thought to play a major role in cocaine craving and relapse. Incentive motivational effects of cocaine and cocaine cues involve dopamine (DA), serotonin (5-HT), and glutamate systems. Furthermore, there is mounting evidence that suggests cocaine and cocaine cues activate different, but overlapping neural circuits and much attention has been given to understanding the role of DA and glutamate within these circuits. In contrast, little research has examined the role of 5-HT in these circuits. Recent research suggests that stimulation of 5-HT2C receptors (Rs) inhibits mesolimbic DA neurons and decreases the incentive motivational effects of both cocaine and cues, whereas stimulation of 5-HT2ARs may facilitate incentive motivational effects of these stimuli. The proposed research will examine specific hypotheses regarding the anatomical locus of these effects. Specifically, we hypothesize that increased stimulation of 5-HT2CRs in the amygdala inhibits incentive motivational effects of cocaine cues, whereas stimulation of these receptors in the ventral tegmental area inhibits incentive motivational effects of both cues and cocaine itself. Furthermore, we hypothesize that stimulation of 5-HT2CRs in the medial prefrontal cortex inhibits the incentive motivational effects of these stimuli, whereas stimulation of 5-HT2ARs in this region facilitates the effects. The hypotheses will be tested by examining the effects of localized infusions of 5-HT drugs on reinstatement of extinguished cocaine-seeking behavior (i.e., operant responding in the absence of cocaine reinforcement) following cocaine priming injections or exposure to cocaine cues. Contingent upon support for predicted effects, subsequent experiments will examine the anatomical and pharmacological specificity of the effects. This research will help to elucidate the role of 5-HT in the neural circuits underlying incentive motivational effects of cocaine and cocaine cues. Understanding these circuits will likely have important implications for developing treatments for cocaine dependence.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Lynch, Minda
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Arizona State University-Tempe Campus
Schools of Arts and Sciences
United States
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Der-Ghazarian, Taleen S; Call, Tanessa; Scott, Samantha N et al. (2017) Effects of a 5-HT1B Receptor Agonist on Locomotion and Reinstatement of Cocaine-Conditioned Place Preference after Abstinence from Repeated Injections in Mice. Front Syst Neurosci 11:73
Garcia, Raul; Cotter, Austin R; Leslie, Kenneth et al. (2017) Preclinical Evidence That 5-HT1B Receptor Agonists Show Promise as Medications for Psychostimulant Use Disorders. Int J Neuropsychopharmacol 20:644-653
Peartree, Natalie A; Hatch, Kayla N; Goenaga, Julianna G et al. (2017) Social context has differential effects on acquisition of nicotine self-administration in male and female rats. Psychopharmacology (Berl) 234:1815-1828
Wang, Junshi; Bastle, Ryan M; Bass, Caroline E et al. (2016) Overexpression of BDNF in the ventral tegmental area enhances binge cocaine self-administration in rats exposed to repeated social defeat. Neuropharmacology 109:121-130
Bastle, Ryan M; Peartree, Natalie A; Goenaga, Julianna et al. (2016) Immediate early gene expression reveals interactions between social and nicotine rewards on brain activity in adolescent male rats. Behav Brain Res 313:244-254
Kufahl, Peter R; Peartree, Natalie A; Heintzelman, Krista L et al. (2015) Region-specific effects of isoflurane anesthesia on Fos immunoreactivity in response to intravenous cocaine challenge in rats with a history of repeated cocaine administration. Brain Res 1594:256-66
Pentkowski, Nathan S; Harder, Bryan G; Brunwasser, Samuel J et al. (2014) Pharmacological evidence for an abstinence-induced switch in 5-HT1B receptor modulation of cocaine self-administration and cocaine-seeking behavior. ACS Chem Neurosci 5:168-76
Neisewander, Janet L; Cheung, Timothy H C; Pentkowski, Nathan S (2014) Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development. Neuropharmacology 76 Pt B:301-19
Bardo, M T; Neisewander, J L; Kelly, T H (2013) Individual differences and social influences on the neurobehavioral pharmacology of abused drugs. Pharmacol Rev 65:255-90
Brackney, Ryan J; Cheung, Timothy H C; Herbst, Katrina et al. (2012) Extinction learning deficit in a rodent model of attention-deficit hyperactivity disorder. Behav Brain Funct 8:59

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