The primary objective of this project is to understand the neuronal, cellular and synaptic mechanisms underlying alcohol intoxication and dependence, using intracellular and patch-clamp recording in brain slices and in vivo microdialysis. A central hypothesis is that adaptive changes in synapses cause alcohol dependence. We also hypothesize that neuroadaptations in the GABAergic system play a major role in alcohol reinforcing actions. Our past research has centered on neurons of the central nucleus of the amygdala (CeA), because behavioral studies suggest that the amygdala, and its connections to the NAcc and bed nucleus of the stria terminalis, termed the 'extended amygdala,'play a major role in the acute reinforcing effects of ethanol and in the anxiogenic response to ethanol withdrawal. Our planned studies are based on the following rationale: 1) Acute ethanol markedly enhances GABAergic neurotransmission in CeA through the activation of CRF1 receptors. We present the first direct evidence that this ethanol-induced increase in GABAergic response is in part due to increased GABA release. 2) Our preliminary data also indicate that chronic ethanol treatment (GET) greatly enhances baseline GABAergic tone in the CeA. 3) Despite this large increase in basal GABA release, there is a lack of tolerance to acute ethanol-induced GABA release in CeA of GET rats. 4) Our preliminary evidence of neuroadaptive changes in the CRF system and in GABAB receptors in modulating synaptic efficacy following GET. Therefore in this application we propose to study the cellular and molecular basis of ethanol interactions with GABAergic transmission using a multidisciplinary approach.
Specific Aims 1 and 2 will test, in vitro and in vivo, the possible involvement of presynaptic CRF receptors, membrane Ca++ channel and their transduction mechanisms coupled to the regulation of GABA release machinery in the effect of acute (Aim 1) and chronic (Aim2) ethanol in CeA neurons. Understanding the specific presynaptic mechanisms underlying ethanol enhancement of GABA IPSPs induced by both acute and chronic ethanol represents a new challenge for alcohol research and a possible target for the development of therapeutic compounds 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 #
5R01AA015566-08
Application #
8387716
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2005-12-05
Project End
2014-07-31
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
8
Fiscal Year
2013
Total Cost
$256,475
Indirect Cost
$121,132
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