The Cellular Electrophysiology Project (Director: Marisa Roberto, Co-Director: George Siggins) proposes to continue cellular studies of the role of neurotransmission in alcohol drinking and dependence and is based on behavioral findings that the basolateral (BLA) and central (CeA) amygdala nuclei are key brain areas involved in stress reactions and alcohol dependence. This renewal application will focus on the overall hypotheses that the transition from low levels of drinking to chronic binge drinking is driven by decreased activity in endocannabinoid systems in ?reward circuits? in the amygdala and that the transition from binge drinking to dependence is also driven by recruitment of a dysregulated stress system driven by corticotropinreleasing factor (CRF) and the neuronal pentraxin Narp. We will use amygdala slice preparations to functionally and morphologically characterize CeA and BLA neurons (Specific Aims 1 and 2) and neurocircuitry (Specific Aims 1-3) involved in responses to ethanol, cannabinoids, and CRF and in the progression from binge drinking to dependence.
Specific Aim 1 is designed to test the hypothesis that binge drinking and/or dependence will differentially alter responses to cannabinoids (CB1 receptor agonists and antagonists) in specific neurons and synapses in the BLA and CeA.
Specific Aim 2 will test the hypothesis that withdrawal from alcohol bingeing or dependence will alter synaptic glutamatergic transmission both within and between the BLA and CeA and/or their responses to CRF and acute ethanol via changes in Narp levels.
Specific Aim 3 is designed to use neuronal filling with biocytin and tracing via retrograde labeling from brain-region targets of BLA and CeA neurons, such as the bed nucleus of stria terminalis, to test the hypothesis that alterations in synaptic properties within specific neurons and neurocircuitries are involved in binge drinking, dependence, and withdrawal and may be associated with changes in the endocannabinoid and CRF or Narp systems. This project will use BLA and CeA brain slices and standard intracellular and whole-cell clamp methods and a battery of measures to assess the pre- vs. postsynaptic sites of action of ethanol and ligand effects and will involve collaborations with the Parsons, Zorrilla, and Mandyam components and Viral Vector and Animal Models/Biological Measurement Cores. The project should provide important new information on the possible sequelae of ethanol binge drinking to dependence at the cellular, microcircuitry, synaptic, and ion channel levels.

Public Health Relevance

This project will examine the cellular and synaptic mechanisms in the amygdala likely to underlie binge alcohol drinking and alcohol dependence. Because such mechanisms are also integrated within several other TSRI Alcohol Research Center projects and involve potentially ?druggable? sites, the present studies represent new directions in attempts to validate drug targets for the prevention or treatment of binge drinking and dependence on alcohol

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
2P60AA006420-30
Application #
8401584
Study Section
Special Emphasis Panel (ZAA1-GG (50))
Project Start
Project End
Budget Start
2013-02-10
Budget End
2013-12-31
Support Year
30
Fiscal Year
2013
Total Cost
$229,864
Indirect Cost
$108,564
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Logrip, Marian L; Oleata, Christopher; Roberto, Marisa (2017) Sex differences in responses of the basolateral-central amygdala circuit to alcohol, corticosterone and their interaction. Neuropharmacology 114:123-134
Natividad, Luis A; Buczynski, Matthew W; Herman, Melissa A et al. (2017) Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype. Biol Psychiatry 82:500-510
Kimbrough, Adam; de Guglielmo, Giordano; Kononoff, Jenni et al. (2017) CRF1 Receptor-Dependent Increases in Irritability-Like Behavior During Abstinence from Chronic Intermittent Ethanol Vapor Exposure. Alcohol Clin Exp Res 41:1886-1895
Mason, Barbara J (2017) Emerging pharmacotherapies for alcohol use disorder. Neuropharmacology 122:244-253
Luczak, Susan E; Liang, Tiebing; Wall, Tamara L (2017) Age of Drinking Initiation as a Risk Factor for Alcohol Use Disorder Symptoms is Moderated by ALDH2*2 and Ethnicity. Alcohol Clin Exp Res 41:1738-1744
Irimia, Cristina; Buczynski, Matthew W; Natividad, Luis A et al. (2017) Dysregulated Glycine Signaling Contributes to Increased Impulsivity during Protracted Alcohol Abstinence. J Neurosci 37:1853-1861
Melroy-Greif, Whitney E; Wilhelmsen, Kirk C; Yehuda, Rachel et al. (2017) Genome-Wide Association Study of Post-Traumatic Stress Disorder in Two High-Risk Populations. Twin Res Hum Genet 20:197-207
Varodayan, Florence P; Bajo, Michal; Soni, Neeraj et al. (2017) Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala. Addict Biol 22:766-778
Roberto, Marisa; Varodayan, Florence P (2017) Synaptic targets: Chronic alcohol actions. Neuropharmacology 122:85-99
Varodayan, Florence P; de Guglielmo, Giordano; Logrip, Marian L et al. (2017) Alcohol Dependence Disrupts Amygdalar L-Type Voltage-Gated Calcium Channel Mechanisms. J Neurosci 37:4593-4603

Showing the most recent 10 out of 184 publications