This Mentored Career Development Award (K01) will support Dr. Rodrigo A. Espana's long-term career objective of establishing an independent systems neuroscience program within an academic setting. Dr. Espana is interested in the actions of neuromodulators on arousal and motivated behaviors. In the proposed research program, Dr. Espana will utilize self-administration, microdialysis, and voltammetric techniques to examine the contribution of the excitatory neuropeptide hypocretin/orexin to reward and addiction processing. Cocaine addiction is a chronic relapsing disease characterized by repetitive, compulsive drug abuse despite negative physical, psychological, and social consequences. Despite huge advances in the neuroscience of drug abuse, available drugs for the treatment of cocaine addiction are ineffective or intolerable and consequently no approved pharmacotherapies currently exist. The hypocretins are relatively recently identified neuropeptides that participate in the regulation of arousal, locomotor activity, and a variety of motivated behaviors. Recently, emerging evidence indicates that the hypocretin system exerts a facilitatory influence on reward function and that these actions involve activation of dopamine neurons of the ventral tegmental area. Given the potential that the hypocretin system regulates reward associated with drug abuse, the proposed research program will employ a multidisciplinary approach to investigate hypocretin modulation of cocaine self-administration and the dopaminergic correlates that underlie these actions. To characterize the contribution of hypocretin systems in the regulation of arousal and motivated behaviors, particularly as it relates to drug abuse, this proposal will investigate: 1) The extent to which the hypocretin system influences cocaine-self administration;2);Whether the hypocretin system participates in cocaine-induced dopamine release within the nucleus accumbens;and 3) To what degree the hypocretin systems regulates spontaneous dopamine spike activity within the nucleus accumbens. Completion of this work will provide information on the extent to which hypocretin participates in reward processing, the extent to which these actions involve the mesolimbic DA system, and will offer insight into the neural mechanisms underlying the addiction process. Further the results obtained from these studies may form the foundations to generate novel pharmacotherapies for drug abuse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Scientist Development Award - Research & Training (K01)
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Human Development Research Subcommittee (NIDA)
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Frankenheim, Jerry
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Wake Forest University Health Sciences
Schools of Medicine
United States
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Brodnik, Zachary D; España, Rodrigo A (2015) Dopamine uptake dynamics are preserved under isoflurane anesthesia. Neurosci Lett 606:129-34
Brodnik, Zachary D; Bernstein, David L; Prince, Courtney D et al. (2015) Hypocretin receptor 1 blockade preferentially reduces high effort responding for cocaine without promoting sleep. Behav Brain Res 291:377-384
Prince, Courtney D; Rau, Andrew R; Yorgason, Jordan T et al. (2015) Hypocretin/Orexin regulation of dopamine signaling and cocaine self-administration is mediated predominantly by hypocretin receptor 1. ACS Chem Neurosci 6:138-46
Ferris, Mark J; España, Rodrigo A; Locke, Jason L et al. (2014) Dopamine transporters govern diurnal variation in extracellular dopamine tone. Proc Natl Acad Sci U S A 111:E2751-9
Ferris, Mark J; Calipari, Erin S; Melchior, James R et al. (2013) Paradoxical tolerance to cocaine after initial supersensitivity in drug-use-prone animals. Eur J Neurosci 38:2628-36
Espana, Rodrigo A; Jones, Sara R (2013) Presynaptic dopamine modulation by stimulant self-administration. Front Biosci (Schol Ed) 5:261-76
España, Rodrigo A (2012) Hypocretin/orexin involvement in reward and reinforcement. Vitam Horm 89:185-208
Calipari, Erin S; España, Rodrigo A (2012) Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms. Front Behav Neurosci 6:54
Oleson, Erik B; Ferris, Mark J; España, Rodrigo A et al. (2012) Effects of the histamine H? receptor antagonist and benztropine analog diphenylpyraline on dopamine uptake, locomotion and reward. Eur J Pharmacol 683:161-5
Yorgason, J T; Jones, S R; Espana, R A (2011) Low and high affinity dopamine transporter inhibitors block dopamine uptake within 5 sec of intravenous injection. Neuroscience 182:125-32

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