2008 — 2011 |
Salinas, Armando |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Central Amygdala Cart Modulates Ethanol Withdrawal Induced Anxiety @ University of Texas Austin
[unreadable] DESCRIPTION (provided by applicant): Ethanol dependence is a widespread affliction with societal costs in the hundreds of billions of dollars every year. Treatment of ethanol dependence is complicated by many factors, most notably relapse. Relapse behaviors are believed to result from ethanol withdrawal-induced anxiety (EWIA). A brain region critically involved in EWIA is the central amygdala (CeA). Lesions of the central, but not basolateral, amygdala resulted in reduced ethanol consumption during withdrawal. Neurobiological alterations induced by ethanol dependence are widespread; in the CeA, these changes include increased glutamatergic activity and NMDA receptor expression. During withdrawal, these increases lead to hyperactivation of the CeA; this hyperactivation is believed to mediate the withdrawal-induced anxiety that underlies relapse. Cocaine- and amphetamine-regulated transcript (CART) is a novel neuropeptide implicatied in ethanol dependence. It is expressed in the CeA and has been shown to increase expression here during acute withdrawal. Additionally, CART, has been reported to potentiate NMDA receptor-mediated currents. The overarching hypothesis of this proposal is that CART is a critical mediator of EWIA. To test this, a comprehensive examination of CART expression during dependence and withdrawal will be conducted. Ethanol dependence will-be induced using two models: chronic ethanol treatment (CET) and chronic intermittent ethanol (CIE). CIE contains a withdrawal component that presumably involves withdrawal induced anxiety. Dependence liability in wild type (WT) and CART knockout (KO) mice will compared using both CET and CIE. An examination of EWIA in the WT and KO mice at 0, 24, and 72 hours withdrawal will also be conducted. Corticosterone ELISAs and immunohistochemistry will be performed as well. Stress induced drinking and corticosterone levles in response to an acute stressor will also be assessed and compared between the WT and KO mice. The second half of this proposal will first verify in our hands, the NMDA potentiating actions of CART, specifically in the CeA. Then, a comprehensive electrophysiological voltage clamp analysis and comparison of NMDA receptor-mediated currents in the CeA of ethanol naive, CET, and CIE mice at 0, 24, and 72 hours withdrawal in WT and KO mice will be performed. The findings from these experiments will elucidate the underpinnings of EWIA and the role of CART in EWIA-induced relapse. Furthermore, these results will provide a novel target for therapeutic intervention and prevention of relapse in individuals dependent on ethanol and possibly other drugs of abuse. [unreadable] [unreadable] [unreadable]
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0.942 |
2018 — 2020 |
Salinas, Armando |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. |
Chronic Ethanol Effects On Cholinergic Interneurons of the Striatum @ George Mason University
Project Summary: The striatum is implicated in learning, reward and addiction, including alcoholism. Within the striatum, ablation of cholinergic interneurons (CINs) results in behavioral and cognitive deficits similar to those observed in alcoholics. Interestingly, there is evidence indicating a decrease in CINs following chronic ethanol exposure. In agreement, I have found that striatal cholinergic function is impaired in monkeys following long-term ethanol consumption. Therefore, the overarching hypothesis of this proposal is that chronic ethanol exposure decreases striatal CIN numbers or function and that these ethanol-induced cholinergic impairments underlie the behavioral and cognitive deficits associated with alcoholism. To test this hypothesis, I propose three specific aims: Specific Aim 1 ? I will determine the effect of acute ethanol on striatal CIN subtypes using transgenic mice, immunohistochemical, RNAscope, and electrophysiological techniques. The characterization of CIN subtype sensitivity to ethanol will be of broad interest to alcohol and basal ganglia researchers alike. Specific Aim 2 ? I will determine if chronic ethanol-induced deficits in striatal CINs are due to a loss of CINs, an impairment of CIN function, or both. There is agreement in the literature that the striatal cholinergic circuit is hypo-functional following chronic ethanol exposure but the source of this dysfunction is not clear. Therefore, I will determine if CINs are lost and/or if CIN function is compromised (with electrophysiology) following chronic ethanol exposure. These results will be the first to examine the effects of chronic ethanol on striatal CIN function. Specific Aim 3 ? I will then determine if in vivo chemogenetic manipulation of CIN activity after chronic ethanol are sufficient to ameliorate the behavioral and cognitive deficits that accompany chronic ethanol exposure including ethanol consumption and performance on an operant reversal learning task. Throughout my career, I have been interested in the mechanisms underlying normal and aberrant behaviors. I have been fortunate to have mentors that taught me the skills required to engage in meaningful research. At every stage of my career, I have advanced in my technical ability and scientific sophistication and as I continue to train, my mentors, Kim Blackwell and David Lovinger, will challenge me to constantly improve as a scientist and to ask impactful questions, to design compelling experiments to address those questions, and to present my findings clearly and effectively in manuscripts and presentations. Furthermore, we have a plan to ensure that I receive training to conduct exciting experiments, run a successful lab, and mentor trainees. In addition, Drs. Adron Harris and Marisa Roberto, two successful researchers, have agreed to serve on my advisory committee to ensure that I am successful in my transition to an independent investigator. Thus, I am confident that with the mentorship of my mentors, my extramural advisory committee, my technical consultants, and the institutional support of NIAAA and George Mason University, I will be able to execute the proposed experiments, attain a faculty position, and thrive as a successful independent neuroscientist.
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