The central nucleus of the amygdala (CeA) functions as a hub that converts emotionally relevant sensory information into appropriate behavioral and physiological responses, and plays a crucial role in anxiety-like behavior associated with ethanol dependence and withdrawal. Notably, both the corticotropin-releasing factor (CRF) and norepinephrine (NE) systems are critical in behavioral aspects of addiction, including the anxiogenic effects of drug withdrawal. We hypothesize that ethanol dependence induces neuroadaptations in the CeA and that many of these neuroadaptations may persist after cessation of ethanol exposure. Therefore, we propose to investigate whether or not the changes in signal transduction and synaptic functions seen in the CeA persist after prolonged ethanol withdrawal (abstinence) for 1 and 2 weeks. The previous funding period identified critical findings in the understanding of acute alcohol effects and alcohol dependence in the medial subdivision of the CeA. We demonstrated that corticotropin-releasing factor 1 (CRF1) receptors are involved in the ethanol-induced increase in GABA release in CeA and the CRF system is up-regulated after ethanol dependence. Notably, chronic CRF1 antagonist treatment blocked alcohol dependence-induced increases in ethanol consumption. Both the protein kinase C epsilon (PKCepsilon) and adenylate cyclase/protein kinase A (AC/PKA) transduction pathways are involved in mediating the CRF and ethanol effects on GABA release. Ethanol dependence downregulated the GABAB system and gabapentin (a structural analogue of GABA) reversed several behavioral aspects of ethanol dependence. We also identified long-lasting neuroadaptations induced by ethanol dependence in the glutamatergic systems. Based on these combined findings, the research plan of the present competitive renewal will be to continue studying (in vitro and in vivo) the presynaptic mechanisms of ethanol and the neuroadaptations within the CeA during the development of alcohol dependence, with a focus on newly identified intracellular pathways involved in ethanol, CRF and NE effects in the CeA. Since there is no data on the persistence of such neuroadaptive changes after cessation of ethanol exposure, we propose to study neural function during ethanol abstinence and characterize how long those neuroadaptative changes last. The general hypothesis is that chronic ethanol and dependence alter the CRF and NE systems and their effects on CeA GABA and glutamate signaling through common cellular systems to induce a maladaptation in neural function that sensitizes ethanol withdrawal-induced anxiety-like behavior. Given the extreme importance of this observation, it is imperative to provide data that can elucidate the cellular basis of the susceptibility of alcoholics to stress and relapse. A better understanding of the neuroadaptations shaping the synaptic networks involved in ethanol dependence represents a challenge to alcohol researchers and will be useful toward uncovering new therapeutic agents to alleviate alcohol dependence and prevent relapse.

Public Health Relevance

Despite the importance of the corticotropin-releasing factor and norepinephrine systems in behavioral aspects of drug addiction and withdrawal, the neuronal mechanisms involved in their effects in the amygdala have not been fully delineated. Thus, the present competitive renewal will measure the neuroadaptive changes induced by ethanol dependence and withdrawal in these systems in the amygdala. Determining critical neuroadaptions, and their persistence after ethanol exposure, may be invaluable in the development of pharmacotherapeutics for the treatment of alcoholism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Liu, Qi-Ying
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Scripps Research Institute
La Jolla
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Herman, Melissa Ann; Roberto, Marisa (2014) Cell-type-specific tonic GABA signaling in the rat central amygdala is selectively altered by acute and chronic ethanol. Addict Biol :
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Cruz, Maureen T; Herman, Melissa A; Kallupi, Marsida et al. (2012) Nociceptin/orphanin FQ blockade of corticotropin-releasing factor-induced gamma-aminobutyric acid release in central amygdala is enhanced after chronic ethanol exposure. Biol Psychiatry 71:666-76
Gilpin, Nicholas W; Roberto, Marisa (2012) Neuropeptide modulation of central amygdala neuroplasticity is a key mediator of alcohol dependence. Neurosci Biobehav Rev 36:873-88

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