This is a competitive U01 renewal application under the Integrative Neuroscience Initiative on Alcoholism- Neuroimmune (INIA-N) consortium (Notice# RFA-AA-16-004/5/6) to identify the role of immune signaling in ethanol dependence and develop new therapeutic strategies for the treatment of alcoholism. This U01 component will provide critical information on cellular mechanisms and neurobiological targets to other INIA- N investigators to bridge alcohol basic research with the human condition. Genetic evidence from INIA-N indicates that immune-related pathways, including interleukin-1? (IL-1?) and IL-10, are altered in alcohol dependence. Our recent results show that cytokines strongly influence neuronal function by modulating GABA neurotransmission in the central amygdala (CeA), a brain region involved in excessive drinking and ethanol dependence. The medial prefrontal cortex (mPFC) is also involved in the development of ethanol dependence and displays differences in its immune responses to chronic alcohol treatment; a stronger immune response is elicited in the cortex compared with the CeA. Our hypothesis is that alcohol exposure dysregulates neuroimmune mechanisms, leading to a general upregulation of proinflammatory elements and downregulation of antiinflammatory elements that contribute to altered synaptic transmission and alcohol-related behaviors. Thus, in this renewal, in addition to the focus on proinflammatory elements (such as IL-1?) we will investigate antiinflammatory systems (IL-10, IL-1ra) in the CeA and mPFC.
In Aim 1 and 2, to induce ethanol dependence, we will use the chronic intermittent ethanol?two-bottle choice (CIE-2BC) paradigm in both male and female mice. We will apply behavioral, biochemical, and electrophysiological approaches to characterize dysregulation of the pro- and antiinflammatory mechanisms in alcohol-drinking animals.
Aim 3 will provide behavioral and electrophysiological testing of the effects of ethanol-induced neuroimmune responses on physiological functions across species (rodents and nonhuman primates) and cellular and molecular mechanisms of the candidate drugs that are identified by other INIA-N projects in selected animal models. Thus, we anticipate that our studies will identify the role and mechanisms of action of neuroimmune factors in excessive alcohol drinking. Our collaborations with the other INIA-N PIs will promote replicability and translational aspects of our studies by testing our key targets in multiple species using multiple complementary approaches. The key personnel involved in this proposal possess all of the necessary expertise to accomplish this multidisciplinary program. Drs. M. Roberto and M. Bajo will be dedicated to the electrophysiology and biochemical studies, and Dr. A. Roberts will perform the behavioral studies. These key personnel each have extensive publication histories in their respective areas of expertise and ongoing collaborative interactions with many other INIA PIs that will be invaluable for the successful completion of the proposed experiments.

Public Health Relevance

INIA-N investigators have shown that brain immune-related pathways are involved in excessive ethanol consumption and that pharmacological intervention with anti-inflammatory drugs reduces drinking. This project will examine the cellular and synaptic mechanisms of alcohol-induced immune responses in the brain that are hypothesized to contribute to excessive drinking. Therefore, the present studies have the potential to identify new therapeutic targets to reduce excessive drinking.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1)
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Liu, Qi-Ying
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Scripps Research Institute
La Jolla
United States
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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
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
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
Roberto, Marisa; Varodayan, Florence P (2017) Synaptic targets: Chronic alcohol actions. Neuropharmacology 122:85-99

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