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 #
3U01AA013498-14S1
Application #
8740365
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Liu, Qi-Ying
Project Start
2001-09-27
Project End
2016-08-30
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kirson, Dean; Oleata, Christopher Shaun; Parsons, Loren Howell et al. (2018) CB1 and ethanol effects on glutamatergic transmission in the central amygdala of male and female msP and Wistar rats. Addict Biol 23:676-688
Huitron-Resendiz, Salvador; Nadav, Tali; Krause, Stephanie et al. (2018) Effects of Withdrawal from Chronic Intermittent Ethanol Exposure on Sleep Characteristics of Female and Male Mice. Alcohol Clin Exp Res 42:540-550
Varodayan, F P; Khom, S; Patel, R R et al. (2018) Role of TLR4 in the Modulation of Central Amygdala GABA Transmission by CRF Following Restraint Stress. Alcohol Alcohol 53:642-649
McClatchy, Daniel B; Yu, Nam-Kyung; Martínez-Bartolomé, Salvador et al. (2018) Structural Analysis of Hippocampal Kinase Signal Transduction. ACS Chem Neurosci :
Varodayan, Florence P; Sidhu, Harpreet; Kreifeldt, Max et al. (2018) Morphological and functional evidence of increased excitatory signaling in the prelimbic cortex during ethanol withdrawal. Neuropharmacology 133:470-480
Blasio, Angelo; Wang, Jingyi; Wang, Dan et al. (2018) Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice. Biol Psychiatry 84:193-201
Roberto, Marisa; Spierling, Samantha R; Kirson, Dean et al. (2017) Corticotropin-Releasing Factor (CRF) and Addictive Behaviors. Int Rev Neurobiol 136:5-51
Borghese, Cecilia M; Herman, Melissa; Snell, Lawrence D et al. (2017) Novel Molecule Exhibiting Selective Affinity for GABAA Receptor Subtypes. Sci Rep 7:6230
Bray, Jennifer G; Roberts, Amanda J; Gruol, Donna L (2017) Transgenic mice with increased astrocyte expression of CCL2 show altered behavioral effects of alcohol. Neuroscience 354:88-100
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

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