Endogenous opioid systems are increasingly recognized as important regulators of basal hedonic homeostasis and as significant factors mediating acute and chronic responses to multiple drugs in addition to opiates. Our previous work has emphasized the role of enkephalins, acting through mu opioid receptors in mediating the opioid component of basal "hedonic tone". We propose to extend these studies to examine the role such systems play in controlling acute behavioral responses to cocaine, whether administered non-contingently or self-administered. The rewarding and reinforcing effects of cocaine will be studied in mu and delta opioid receptor null mice and in mice deficient in pro-enkephalin or B-endorphin using the conditioned place preference and operant self- administration paradigms. In addition to evaluating the acute effects of cocaine in such opioid-deficient mice, we will examine these mice for anomalies in sensitized motivational responses to repeated non-contingent cocaine administration and for propensity to reinstate drug-seeking following prolonged extinction of such behavior. The loci within the brain wherein these endogenous opioid-mediated phenomena originate will be explored by two parallel approaches focusing initially on the ventral pallidum and nucleus accumbens: 1) attempts to reverse phenotypes observed in opioid receptor null mice will be made by local, lentiviral-mediated, expression of the receptor and 2) evidence of changes in opioid peptide release in these structures during various stages of cocaine exposure will be explored using microdialysis combined with mass spectrometry.Project Narrative These studies will increase our understanding of the neurochemical underpinnings of relapse following prolonged abstinence. These are key issues for the development of effective medications to treat cocaine addiction and the information gleaned from these studies will likely generalize to other classes of abused substances.

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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Sorensen, Roger
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Wassum, Kate M; Greenfield, Venuz Y; Linker, Kay E et al. (2014) Inflated reward value in early opiate withdrawal. Addict Biol :
Ostlund, Sean B; Kosheleff, Alisa R; Maidment, Nigel T (2014) Differential effects of systemic cholinergic receptor blockade on Pavlovian incentive motivation and goal-directed action selection. Neuropsychopharmacology 39:1490-7
LeBlanc, Kimberly H; Maidment, Nigel T; Ostlund, Sean B (2014) Impact of repeated intravenous cocaine administration on incentive motivation depends on mode of drug delivery. Addict Biol 19:965-71
Ostlund, Sean B; LeBlanc, Kimberly H; Kosheleff, Alisa R et al. (2014) Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure. Neuropsychopharmacology 39:2441-9
Ostlund, Sean B; Kosheleff, Alisa; Maidment, Nigel T et al. (2013) Decreased consumption of sweet fluids in * opioid receptor knockout mice: a microstructural analysis of licking behavior. Psychopharmacology (Berl) 229:105-13
Wassum, Kate M; Ostlund, Sean B; Loewinger, Gabriel C et al. (2013) Phasic mesolimbic dopamine release tracks reward seeking during expression of pavlovian-to-instrumental transfer. Biol Psychiatry 73:747-55
LeBlanc, Kimberly H; Maidment, Nigel T; Ostlund, Sean B (2013) Repeated cocaine exposure facilitates the expression of incentive motivation and induces habitual control in rats. PLoS One 8:e61355
Wassum, Kate M; Ostlund, Sean B; Maidment, Nigel T (2012) Phasic mesolimbic dopamine signaling precedes and predicts performance of a self-initiated action sequence task. Biol Psychiatry 71:846-54
Wassum, Kate M; Tolosa, Vanessa M; Tseng, Tina C et al. (2012) Transient extracellular glutamate events in the basolateral amygdala track reward-seeking actions. J Neurosci 32:2734-46
Laurent, Vincent; Leung, Beatrice; Maidment, Nigel et al. (2012) ýý- and ýý-opioid-related processes in the accumbens core and shell differentially mediate the influence of reward-guided and stimulus-guided decisions on choice. J Neurosci 32:1875-83

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