The Cellular Electrophysiology Project (Director: Marisa Roberto, Co-Director: George Siggins) proposes to continue cellular studies of the role of neurotransmission in alcohol drinking and dependence and is based on behavioral findings that the basolateral (BLA) and central (CeA) amygdala nuclei are key brain areas involved in stress reactions and alcohol dependence. This renewal application will focus on the overall hypotheses that the transition from low levels of drinking to chronic binge drinking is driven by decreased activity in endocannabinoid systems in ?reward circuits? in the amygdala and that the transition from binge drinking to dependence is also driven by recruitment of a dysregulated stress system driven by corticotropinreleasing factor (CRF) and the neuronal pentraxin Narp. We will use amygdala slice preparations to functionally and morphologically characterize CeA and BLA neurons (Specific Aims 1 and 2) and neurocircuitry (Specific Aims 1-3) involved in responses to ethanol, cannabinoids, and CRF and in the progression from binge drinking to dependence.
Specific Aim 1 is designed to test the hypothesis that binge drinking and/or dependence will differentially alter responses to cannabinoids (CB1 receptor agonists and antagonists) in specific neurons and synapses in the BLA and CeA.
Specific Aim 2 will test the hypothesis that withdrawal from alcohol bingeing or dependence will alter synaptic glutamatergic transmission both within and between the BLA and CeA and/or their responses to CRF and acute ethanol via changes in Narp levels.
Specific Aim 3 is designed to use neuronal filling with biocytin and tracing via retrograde labeling from brain-region targets of BLA and CeA neurons, such as the bed nucleus of stria terminalis, to test the hypothesis that alterations in synaptic properties within specific neurons and neurocircuitries are involved in binge drinking, dependence, and withdrawal and may be associated with changes in the endocannabinoid and CRF or Narp systems. This project will use BLA and CeA brain slices and standard intracellular and whole-cell clamp methods and a battery of measures to assess the pre- vs. postsynaptic sites of action of ethanol and ligand effects and will involve collaborations with the Parsons, Zorrilla, and Mandyam components and Viral Vector and Animal Models/Biological Measurement Cores. The project should provide important new information on the possible sequelae of ethanol binge drinking to dependence at the cellular, microcircuitry, synaptic, and ion channel levels.

Public Health Relevance

This project will examine the cellular and synaptic mechanisms in the amygdala likely to underlie binge alcohol drinking and alcohol dependence. Because such mechanisms are also integrated within several other TSRI Alcohol Research Center projects and involve potentially ?druggable? sites, the present studies represent new directions in attempts to validate drug targets for the prevention or treatment of binge drinking and dependence on alcohol

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
2P60AA006420-30
Application #
8401584
Study Section
Special Emphasis Panel (ZAA1-GG (50))
Project Start
Project End
Budget Start
2013-02-10
Budget End
2013-12-31
Support Year
30
Fiscal Year
2013
Total Cost
$229,864
Indirect Cost
$108,564
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Spierling, Samantha R; Kreisler, Alison D; Williams, Casey A et al. (2018) Intermittent, extended access to preferred food leads to escalated food reinforcement and cyclic whole-body metabolism in rats: Sex differences and individual vulnerability. Physiol Behav 192:3-16
Blasio, Angelo; Wang, Jingyi; Wang, Dan et al. (2018) Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice. Biol Psychiatry 84:193-201
Kirson, Dean; Oleata, Christopher Shaun; Parsons, Loren Howell et al. (2018) CB1 and ethanol effects on glutamatergic transmission in the central amygdala of male and female msP and Wistar rats. Addict Biol 23:676-688
Matzeu, Alessandra; Kallupi, Marsida; George, Olivier et al. (2018) Dynorphin Counteracts Orexin in the Paraventricular Nucleus of the Thalamus: Cellular and Behavioral Evidence. Neuropsychopharmacology 43:1010-1020
de Guglielmo, Giordano; Conlisk, Dana E; Barkley-Levenson, Amanda M et al. (2018) Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats. Pharmacol Biochem Behav 167:36-41
Matzeu, Alessandra; Terenius, Lars; Martin-Fardon, Remi (2018) Exploring Sex Differences in the Attenuation of Ethanol Drinking by Naltrexone in Dependent Rats During Early and Protracted Abstinence. Alcohol Clin Exp Res 42:2466-2478
Kononoff, Jenni; Melas, Philippe A; Kallupi, Marsida et al. (2018) Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood. Sci Rep 8:13893
Verheij, Michel M M; Contet, Candice; Karel, Peter et al. (2018) Median and Dorsal Raphe Serotonergic Neurons Control Moderate Versus Compulsive Cocaine Intake. Biol Psychiatry 83:1024-1035
Schmeichel, Brooke E; Matzeu, Alessandra; Koebel, Pascale et al. (2018) Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats. Neuropsychopharmacology 43:2373-2382
Kononoff, Jenni; Kallupi, Marsida; Kimbrough, Adam et al. (2018) Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats. eNeuro 5:

Showing the most recent 10 out of 211 publications