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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA015566-10
Application #
8762044
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2005-04-01
Project End
2019-07-31
Budget Start
2014-08-20
Budget End
2014-11-30
Support Year
10
Fiscal Year
2014
Total Cost
$142,125
Indirect Cost
$67,125
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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 :
Nimitvilai, Sudarat; Herman, Melissa; You, Chang et al. (2014) Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release. Neuropharmacology 82:28-40
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
Cui, Changhai; Noronha, Antonio; Morikawa, Hitoshi et al. (2013) New insights on neurobiological mechanisms underlying alcohol addiction. Neuropharmacology 67:223-32
Herman, Melissa A; Kallupi, Marsida; Luu, George et al. (2013) Enhanced GABAergic transmission in the central nucleus of the amygdala of genetically selected Marchigian Sardinian rats: alcohol and CRF effects. Neuropharmacology 67:337-48
Herman, Melissa A; Contet, Candice; Justice, Nicholas J et al. (2013) Novel subunit-specific tonic GABA currents and differential effects of ethanol in the central amygdala of CRF receptor-1 reporter mice. J Neurosci 33:3284-98
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

Showing the most recent 10 out of 19 publications