The Scripps Research Institute Alcohol Research Center

The Scripps Research Institute ARC

TSRI ARC

Neurochemistry

Director: Remi Martin-Fardon, Ph.D.

The Neurochemistry Research Component will focus on testing the hypothesis that dysregulated eCB signaling in the BLA and BNST contributes to the affective dysregulation and excessive ethanol consumption associated with ethanol dependence and protracted withdrawal. Endocannabinoids provide robust modulatory feedback on glutamate and GABA release, and disruption of eCB function likely results in dysregulated excitatory and inhibitory signaling. This component complements the goals of the Molecular Neuropharmacology and Cellular Neurobiology Research Components. To test this hypothesis, Specific Aim 1 is designed to characterize the nature and persistence of dysregulated eCB function associated with ethanol dependence and evaluate the influence of this dysregulation on withdrawal-related neurochemistry. Specific Aim 2 is designed to characterize the influence of altered 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (anandamide; AEA) signaling in the CeA, BNST, and BLA on anxiety-like behavior during acute and protracted ethanol withdrawal. Specific Aim 3 is designed to evaluate the effect of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) inhibition on ethanol consumption in dependent and nondependent rats. This component will utilize the Animal Models/Biochemical Measures Core and Viral Vector Core and collaborate with the Roberto/Siggins component.             The Clinical Neurobehavioral Research Component (Director: Cindy Ehlers, Ph.D.) will focus on the hypothesis that risk and protective factors for binge drinking and alcohol use disorders can be identified and quantified in Mexican-American young adults and that acculturation stress plays a key role as a risk factor for the development of alcoholism in Mexican-American young adults. This component will build on previous work in this Mexican-American population. Specific Aim 1 is designed to assess a community sample of young adult Mexican-American men and women (total n = 600; 18-30 years old; wave 1) and follow them up at 5-10 years (wave 2) using the Semi-Structured Assessment of the Genetics of Alcoholism (SSAGA) and other select instruments. Specific Aim 2 is designed to collect electrophysiological measures from all new and a select sample of returning participants (electroencephalography [EEG], event-related potentials [ERPs], prepulse inhibition [PPI], event-related oscillations) to determine their association with individual differences in the alcohol phenotype and endophenotypes. Specific Aim 3 is designed to collect DNA from all new participants to assess select candidate genes (ADH, ALDH1, CHRM4, GABAA, OPRM1, CNR1, COMT, DRD2, CRF, NPY) and their association with alcohol use and electrophysiological measures. Specific Aim 4 is designed to test the hypothesis that unique biobehavioral risk factors coupled with excessive alcohol drinking in young adult Mexican Americans produce a disruption in key physiological systems that regulate sleep, arousal, and cognitive function, leading to changes in impulsive and affective behaviors and a cycle of increased drinking and alcohol use disorders. Two models are presented that outline scenarios for the transition from early drinking to binge drinking to dependence. This component also plays a key role in relating to the Center as a whole in that it allows for the “translation” of findings from human studies to rats and vice versa. The measures to help validate the intermittent access (“binge”) and dependence animal models in the Animal Models Core will be the same as those used by the Clinical Neurobehavioral Research Component.