GRANT NUMBER:  U01 AA013498-14S1

ABSTRACT:  This is a proposal in response to the PA-13-275 “Administrative Supplements to Promote Collaborative Research on Addiction at NIH (CRAN): Comorbidity-Related Research” inviting applications seeking for support of research in cross-cutting areas of substance use, abuse, addiction and related health consequences. This supplement will support work within the scope of the original project INIA-West U01 AA013498, where we proposed to use electrophysiological and cytochemical methods to investigate the hypothesis of a role for neuroinflammatory factors in alcohol preference and excessive drinking. In our ongoing studies, we have discovered that the TLR4 system plays a critical role in the ethanol-induced potentiation of GABAergic transmission in the central amygdala (CeA), a key brain area underlying stress reactions and alcohol dependence. We also found that chronic ethanol treatment induces brain region specific activation of the microglia and astrocytes. Alcohol and nicotine addiction develop concurrently and are highly co-morbid in humans. Thus, the studies proposed in this supplement aim to a physiological evaluation of a role of neuroimmune systems in concurrent nicotine- and alcohol addiction with the ultimate goal of identifying pharmacotherapies targeting activated inflammatory signaling in individuals that are dependent. Here, we will test the prediction that simultaneous ethanol and nicotine dependence will synergistically increase activation of inflammatory signaling in the amygdala. Therefore, longterm goals of this application are to [1] assess the possible synergistic activation of specific inflammatory processes in nicotine-alcohol-addiction, [2] understand how neuronal responses to alcohol and nicotine are changed following nicotine and alcohol co-dependence compared to single drug alone, and [3] identify pharmacotherapies with promise for rescuing [excessive] inflammatory signaling activated in individuals that are dependent on nicotine and alcohol. For the critical pharmacotherapeutic mission of the NIAAA and NIDA, these proposed studies represent new steps toward evaluating the cellular sites and mechanisms of action of the emerging neuroinflammatory factors likely involved in nicotine and alcohol co-morbidity in humans.


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