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.
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.
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