This competitive U01 renewal application, under the INIA-West consortium, is based on behavioral findings that the central amygdala (CeA) is a key brain area underlying stress reactions and alcohol dependence, and that these behaviors involve several CeA transmitters (GABA, glutamate) and neuropeptides (CRF, opioids and galanin). Our published electrophysiological studies of these systems in CeA provide an entry point for proposed new studies: a stated need to pursue physiological evaluation of the function of gene products suggested by the molecular components (e.g., of Y. Blednov and others) of the INIA-West to be involved in excessive alcohol drinking. Therefore, we now propose to use electrophysiological and cytochemical methods to investigate the hypothesis of a role for neuroinflammatory factors (lipopolysaccharide {LPS}, toll-like receptor 4 {TLR4}, CD14, cytokines) in alcohol preference and excessive drinking. To test this hypothesis at the cellular level, we propose 4 Specific Aims: 1) To assess the role of TLR4 activation in effects of ethanol and CRF on GABAergic and glutamatergic transmission in CeA slices by LPS superfusion or i.p. injection in CeA of wild type (WT) and CD14 knockout (KO) mice;2) To assess effects of the TLR4-g en e rated inflammatory cytokines IL-ip, TNFa, and IL-6 on membrane and synaptic measures in CeA of WT mice;3) To determine if the LPS, CRF or chronic ethanol increase cytochemical signs of inflammation in CeA;4) To determine if the electrophysiological or cytochemical effects of LPS, cytokines, ethanol or CRF on CeA seen in Specific Aims 1-3 can be reversed by pre-treatment with certain anti-inflammatory drugs. These proposed studies thus represent new steps toward evaluating the cellular sites and mechanisms of action of the emerging gene targets suggested by other INIA West components to underlie alcohol preference or excessive drinking, and may further validate drug targets for reversal or prevention of alcohol effects and excessive drinking.

Public Health Relevance

This project will examine the cellular and synaptic mechanisms likely to underlie the recently discovered inflammatory effects on the brain of alcohol drinking. Because such neuro-inflammatory effects are also suggested to lead to excessive drinking, the present studies also represent a new direction in attempts to validate drug targets for the prevention or treatment of excessive drinking and alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA013498-12
Application #
8327752
Study Section
Special Emphasis Panel (ZAA1-DD (50))
Program Officer
Liu, Qi-Ying
Project Start
2001-09-27
Project End
2016-08-30
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
12
Fiscal Year
2012
Total Cost
$391,811
Indirect Cost
$173,857
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Varodayan, Florence P; Bajo, Michal; Soni, Neeraj et al. (2016) Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala. Addict Biol :
Herman, Melissa A; Sidhu, Harpreet; Stouffer, David G et al. (2015) GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol. Proc Natl Acad Sci U S A 112:7091-6
Repunte-Canonigo, Vez; Herman, Melissa A; Kawamura, Tomoya et al. (2015) Nf1 regulates alcohol dependence-associated excessive drinking and gamma-aminobutyric acid release in the central amygdala in mice and is associated with alcohol dependence in humans. Biol Psychiatry 77:870-9
Bajo, M; Herman, M A; Varodayan, F P et al. (2015) Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic transmission in the central amygdala. Brain Behav Immun 45:189-97
Gilpin, Nicholas W; Herman, Melissa A; Roberto, Marisa (2015) The central amygdala as an integrative hub for anxiety and alcohol use disorders. Biol Psychiatry 77:859-69

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