A great deal of data indicates that orexin (also known as hypocretin) neurons are involved in arousal and narcolepsy. However, we found that that orexin neurons specifically located in lateral hypothalamus (LH) are Fos-activated by cocaine- or morphine-associated stimuli in proportion to the preference that animals express on a conditioned place preference (CPP) test day. Our studies also revealed that chemical stimulation of these cells, or microinfusion of orexin into ventral tegmental area (VTA), reinstates an extinguished drug CPP. Other data from our lab, as well as from other investigators, show that orexin neurotransmission is important for stress-induced reinstatement of drug-self administration, for learning and expressing stimulus-drug relationships, and for glutamate-dependent plasticity in VTA dopamine (DA) neurons. Together, these results provide an important new view on LH orexin projections to midbrain DA neurons, indicating that they play an important role in reward processing and relapse to drug-seeking. The goal of this project is to determine the role of LH orexin neurons and their projections to reward circuitry in the reinstatement of cocaine-seeking following extinction of drug-taking behavior. We will extend our previous CPP studies to the self-administration paradigm and, using anatomical methods, determine if orexin neurons that are activated by cues that induce reinstatement of cocaine-seeking project selectively to one or more areas in reward circuitry. In behavioral experiments with lesions and local microinjections of orexin antagonist, we will also test whether orexin projections from LH to VTA are necessary for cue-induced reinstatment of cocaine-seeking. Finally, using electrophysiological methods, we will examine whether orexin modulates responses of VTA neurons to stimulation of glutamatergic inputs from medial prefrontal cortex. This could reveal mechanisms whereby orexin actions participate in neural plasticity that underlies cueinduced reinstatement of cocaine-seeking. Relevance to public health: Results of these studies will delineate the role of this novel neuropeptide system in cocaine-seeking, and lead to new treatments based upon orexin function that could be effective in maintaining drug abstinence in addicted individuals in the face of cues previously associated with drug taking.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA015369-10
Application #
8377634
Study Section
Special Emphasis Panel (ZDA1-RXL-E)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$180,283
Indirect Cost
$58,402
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Spencer, Sade; Garcia-Keller, Constanza; Roberts-Wolfe, Douglas et al. (2017) Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking. Biol Psychiatry 81:616-624
Bobadilla, Ana-Clara; Garcia-Keller, Constanza; Heinsbroek, Jasper A et al. (2017) Accumbens Mechanisms for Cued Sucrose Seeking. Neuropsychopharmacology 42:2377-2386
Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A et al. (2017) Accumbens nNOS Interneurons Regulate Cocaine Relapse. J Neurosci 37:742-756
Spencer, Sade; Kalivas, Peter W (2017) Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse. Int J Neuropsychopharmacol 20:797-812
Moorman, David E; James, Morgan H; Kilroy, Elisabeth A et al. (2017) Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats. Brain Res 1654:34-42
Barry, Sarah M; McGinty, Jacqueline F (2017) Role of Src Family Kinases in BDNF-Mediated Suppression of Cocaine-Seeking and Prevention of Cocaine-Induced ERK, GluN2A, and GluN2B Dephosphorylation in the Prelimbic Cortex. Neuropsychopharmacology 42:1972-1980
Bobadilla, Ana-Clara; Heinsbroek, Jasper A; Gipson, Cassandra D et al. (2017) Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior. Prog Brain Res 235:93-112
Heinsbroek, Jasper A; Neuhofer, Daniela N; Griffin 3rd, William C et al. (2017) Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking. J Neurosci 37:757-767
Kupchik, Yonatan M; Kalivas, Peter W (2017) The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think. Neuropsychopharmacology 42:369-370
Spencer, Sade; Scofield, Michael; Kalivas, Peter W (2016) The good and bad news about glutamate in drug addiction. J Psychopharmacol 30:1095-1098

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