Substance use disorders have a devastating impact on individuals and their families, with substantial medical and societal impact. Alcoholism is associated with disruptions in circadian rhythms that persist during abstinence and increase risk for relapse. Additionally, genetic variations (SNPs or mutations) in circadian genes have been shown to modulate alcohol consumption, anxiety, depression, and mania in humans. Pre-clinical studies have also revealed that circadian mutations in homologous circadian transcription factors, CLOCK and NPAS2, can alter drug sensitivity and mood-related behaviors. We carry out studies to directly address how brain region and cell specific expression of these genes affects mood- and drug-related behaviors. Findings from these studies will have important translational significance by contributing to our understanding of vulnerability for substance use disorders and susceptibility to relapse.
Substance use disorders are characterized by inability to control intake and high rates of relapse. There exists a serious public health need to identify and characterize new and more effective treatments. Therapies that increase neuronal activity in the nucleus accumbens (NAc) are emerging as a promising treatment tool for alcohol use disorders. However, further research is needed to determine behavioral and molecular consequences of increasing specific brain activity. I am addressing this gap in our knowledge by using genetic and pharmacological approaches to determine the effects of chronic NAc stimulation on the rewarding and aversive aspects of alcohol behaviors, as well as identify treatment responsive gene networks and specific circuitry that underlie lasting reductions in alcohol intake. Findings will provide a great deal of insight into mechanisms underlying the effectiveness of new potential therapies for alcohol use disorders.
My long-term career goals are to move science forward by contributing to the understanding of the molecular mechanisms that underlie addiction and to improved treatment of substance use disorders. Despite advances in neuroscience and psychiatry, we have much to gain in our understanding of substance use disorders and the development of more effective treatments. My specific goals are to: 1) identify mechanisms mediating circadian gene effects on drug- and mood-related behaviors, and 2) identify how altering specific brain activity can alter alcohol-related behaviors and identify transcriptional mechanisms that underlie lasting reductions in binge-like drinking.
We are currently using several complementary approaches in mice to carry out the above research goals: a) clinically relevant drug self-administration models (operant drug self-administration and binge-drinking paradigms), b) viral-mediated gene transfer to temporally and spatially control gene expression and neuronal activity (using DesignerReceptors Exclusively Activated by Designer Drugs, DREADDs), c) behavioral battery of drug and mood-related assays, and d) identification of transcriptional mechanisms and the regulation of gene expression using RNA and ChIP Seq, qPCR, and Western blotting.