Alcohol abuse is a major public health burden in the United States, yet few pharmacotherapies are approved to treat this disease. Naltrexone, a non-selective opioid receptor antagonist, has been effective in clinical trials, as it appears to block the ethanol-evoked activation of brain reward pathways by endogenous opioids. Recent evidence suggests that the A118G polymorphism in exon 1 of the mu-opioid receptor gene (OPRM1) is a clinically relevant risk factor associated with alcohol abuse and dependence. Carrying the G- allele appears to increase the risk of developing alcohol use disorders and predicts treatment response to opioid antagonism in clinical trials, although the etiology of this effect is unclear. This proposal outlines behavioral pharmacology experiments that will employ a humanized mouse model of the A118G polymorphism to determine if sensitivity to the rewarding effects of alcohol is different in mice homozygous for the 118G-allele (h/m118GG) compared to those homozygous for the 118A-allele (h/m118AA). Experiments are also proposed that will determine if the sensitivity of alcohol reward to antagonism by naltrexone differs between h/m118GG and h/m118AA mice. Pharmacological effects of opioids in vitro will be compared between h/m118AA and h/m118GG mice in a site that is critical to alcohol reward to determine if differences in the synaptic effects of opioids may explain behavioral differences in vivo. Intracranial self-stimulation (ICSS), an operant behavioral method, will be used to determine the rewarding effects of alcohol, morphine, and cocaine and to measure the reward-devaluing effects of naltrexone and a kappa-opioid receptor agonist, U69,593. Opioid signaling in the ventral tegmental area, a major target of opioid activity in the brain reward system, will be characterized with whole-cell patch clamp electrophysiology. If funded, these studies will address important unanswered questions about how the A118G polymorphism alters the rewarding effects of alcohol and increase understanding of the mechanism through which this genetic variant increases risk for alcohol abuse. The proposed training plan will provide a solid educational and professional foundation on which to pursue a career as a physician-scientist in the field of addiction medicine.

Public Health Relevance

Alcohol use disorders, which have a strong genetic component, are a major public health burden in the United States. I propose using a humanized mouse model of the clinically-relevant A118G polymorphism in the human mu-opioid receptor gene to investigate pharmacogenetic mechanisms of alcohol reward. These studies may identify cellular mechanisms by which this polymorphism increases the probability of alcohol abuse and predicts therapeutic response to mu-opioid receptor antagonists.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AA021312-03
Application #
8617202
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Egli, Mark
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$32,171
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Robinson, J Elliott; Wolfe, Stephanie M; Kaiser-Rogers, Kathleen et al. (2016) Stroke-Like Presentation Following Febrile Seizure in a Patient with 1q43q44 Deletion Syndrome. Front Neurol 7:67
Vardy, Eyal; Robinson, J Elliott; Li, Chia et al. (2015) A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior. Neuron 86:936-46
Bilbao, Ainhoa; Robinson, J Elliott; Heilig, Markus et al. (2015) A pharmacogenetic determinant of mu-opioid receptor antagonist effects on alcohol reward and consumption: evidence from humanized mice. Biol Psychiatry 77:850-8
Robinson, J Elliott; Vardy, Eyal; DiBerto, Jeffrey F et al. (2015) Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism. Neuropsychopharmacology 40:2614-22
White, Kate L; Robinson, J Elliott; Zhu, Hu et al. (2015) The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. J Pharmacol Exp Ther 352:98-109
Fish, Eric W; DiBerto, Jeffrey F; Krouse, Michael C et al. (2014) Different contributions of dopamine D1 and D2 receptor activity to alcohol potentiation of brain stimulation reward in C57BL/6J and DBA/2J mice. J Pharmacol Exp Ther 350:322-9
Fish, Eric W; Agoglia, Abigail E; Krouse, Michael C et al. (2014) Levetiracetam results in increased and decreased alcohol drinking with different access procedures in C57BL/6J mice. Behav Pharmacol 25:61-70
Fish, Eric W; Whitman, Buddy J; DiBerto, Jeff F et al. (2014) Effects of the neuroactive steroid allopregnanolone on intracranial self-stimulation in C57BL/6J mice. Psychopharmacology (Berl) 231:3415-23
Robinson, J Elliott; Chen, Meng; Stamatakis, Alice M et al. (2013) Levetiracetam has opposite effects on alcohol- and cocaine-related behaviors in C57BL/6J mice. Neuropsychopharmacology 38:1322-33
Fish, Eric W; Krouse, Michael C; Stringfield, Sierra J et al. (2013) Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome. PLoS One 8:e77896

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