Alcohol dependence is a devastating psychiatric disorder to individuals and their families, with substantial medical and societal impact. There exists a serious public health need to identify and characterize new and more effective treatments. Chronic alcohol intake leads to long lasting changes in reward- and stress-related neuronal circuitry. The nucleus accumbens (NAc) is an integral component of this circuitry. The stability of behavioral alterations associated with chronic alcohol abuse suggests maladaptive neuroplasticity that is likely achieved through transcriptional mechanisms. Recent clinical trials have revealed that deep brain stimulation of the NAc decreases alcohol craving and relapse in alcohol dependent subjects (Vogues et al., 2012). Much is unknown about the efficacy and mechanisms underlying treatments that alter brain activity. In the proposed studies, I will use DREADDs (designer receptors exclusively activated by designer drugs) to increase or decrease neuronal activity in the nucleus accumbens and measure alcohol binge drinking (using the limited access paradigm, drinking in the dark) and relapse-like drinking (using chronic intermittent ethanol induction of dependence followed by limited access drinking) behaviors in mice selectively bred to drink intoxicating levels of alcohol in a limited access paradigm. Interestingly, preliminary data reveal that increasing NAc activity decreases binge drinking without altering alcohol reward. Since this is the first time a study such as this has been conducted, it will be essential to determine if these changes in behavior are accompanied by changes in expression of plasticity-related genes and identify DREADD/alcohol responsive gene expression networks using whole transcriptome sequencing (RNA Seq). These findings could have vast implications for alcohol research and treatment.

Public Health Relevance

Substance abuse, including alcohol-related disorders, is a VA Research Priority Area that is a reflection of public health need (since it is among the top 3 diagnoses in the VA Healthcare system) [VA Research Currents, January, 2007]. Although therapies that increase neuronal activity in the nucleus accumbens (an important region for reward) are emerging as a promising therapeutic tool for alcoholism, much is unknown about the efficacy and underlying mechanisms of this kind of therapy. Further research is needed to determine the effects of chronic and specific brain stimulation/inhibition on the motivational aspects of alcohol behaviors, as well as to identify treatment responsive gene networks. To my knowledge, I will be the first person to test whether chronic NAc stimulation or inhibition can decrease or increase, respectively, motivation for alcohol and identify alcohol-DREADD responsive gene networks in a relevant genetic animal model of binge drinking.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
5IK2BX002488-05
Application #
9612480
Study Section
Neurobiology A (NURA)
Project Start
2014-10-01
Project End
2019-09-30
Budget Start
2018-10-01
Budget End
2019-09-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Portland VA Medical Center
Department
Type
DUNS #
089461255
City
Portland
State
OR
Country
United States
Zip Code
97239
Purohit, Kush; Parekh, Puja K; Kern, Joseph et al. (2018) Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge-Like Alcohol Drinking in Mice. Alcohol Clin Exp Res 42:879-888
Ferguson, Laura B; Ozburn, Angela R; Ponomarev, Igor et al. (2018) Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice. Neuropsychopharmacology 43:1257-1266
Ozburn, Angela R; Kern, Joseph; Parekh, Puja K et al. (2017) NPAS2 Regulation of Anxiety-Like Behavior and GABAA Receptors. Front Mol Neurosci 10:360
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Ozburn, Angela R; Purohit, Kush; Parekh, Puja K et al. (2016) Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism. Front Psychiatry 7:67
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