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)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA013498-14
Application #
8708710
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Liu, Qi-Ying
Project Start
Project End
Budget Start
Budget End
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
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
Bajo, Michal; Madamba, Samuel G; Roberto, Marisa et al. (2014) Innate immune factors modulate ethanol interaction with GABAergic transmission in mouse central amygdala. Brain Behav Immun 40:191-202
Ciccocioppo, Roberto; de Guglielmo, Giordano; Hansson, Anita C et al. (2014) Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors. J Neurosci 34:363-72
Kallupi, Marsida; Varodayan, Florence P; Oleata, Christopher S et al. (2014) Nociceptin/orphanin FQ decreases glutamate transmission and blocks ethanol-induced effects in the central amygdala of naive and ethanol-dependent rats. Neuropsychopharmacology 39:1081-92
Cruz, Maureen T; Herman, Melissa A; Cote, Dawn M et al. (2013) Ghrelin increases GABAergic transmission and interacts with ethanol actions in the rat central nucleus of the amygdala. Neuropsychopharmacology 38:364-75
Kang-Park, Maenghee; Kieffer, Brigitte L; Roberts, Amanda J et al. (2013) ?-Opioid receptors in the central amygdala regulate ethanol actions at presynaptic GABAergic sites. J Pharmacol Exp Ther 346:130-7
Cruz, Maureen T; Bajo, Michal; Maragnoli, M Elisabetta et al. (2011) Type 7 Adenylyl Cyclase is Involved in the Ethanol and CRF Sensitivity of GABAergic Synapses in Mouse Central Amygdala. Front Neurosci 4:207
Roberto, Marisa; Cruz, Maureen T; Gilpin, Nicholas W et al. (2010) Corticotropin releasing factor-induced amygdala gamma-aminobutyric Acid release plays a key role in alcohol dependence. Biol Psychiatry 67:831-9
Kang-Park, Maeng-Hee; Kieffer, Brigitte L; Roberts, Amanda J et al. (2009) Mu-opioid receptors selectively regulate basal inhibitory transmission in the central amygdala: lack of ethanol interactions. J Pharmacol Exp Ther 328:284-93
Silberman, Yuval; Bajo, Michal; Chappell, Ann M et al. (2009) Neurobiological mechanisms contributing to alcohol-stress-anxiety interactions. Alcohol 43:509-19

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