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.
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
|Somkuwar, Sucharita S; Fannon, McKenzie J; Staples, Miranda C et al. (2016) Alcohol dependence-induced regulation of the proliferation and survival of adult brain progenitors is associated with altered BDNF-TrkB signaling. Brain Struct Funct 221:4319-4335|
|Curran, H Valerie; Freeman, Tom P; Mokrysz, Claire et al. (2016) Keep off the grass? Cannabis, cognition and addiction. Nat Rev Neurosci 17:293-306|
|Ehlers, Cindy L; Kim, Corinne; Gilder, David A et al. (2016) Lifetime history of traumatic events in a young adult Mexican American sample: Relation to substance dependence, affective disorder, acculturation stress, and PTSD. J Psychiatr Res 83:79-85|
|Melroy-Greif, Whitney E; Wilhelmsen, Kirk C; Ehlers, Cindy L (2016) Genetic variation in FAAH is associated with cannabis use disorders in a young adult sample of Mexican Americans. Drug Alcohol Depend 166:249-53|
|Sobieraj, Jeffery C; Kim, Airee; Fannon, McKenzie J et al. (2016) Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons. Brain Struct Funct 221:261-76|
|de Guglielmo, Giordano; Crawford, Elena; Kim, Sarah et al. (2016) Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala Is Required for Alcohol Dependence. J Neurosci 36:9446-53|
|Buczynski, Matthew W; Herman, Melissa A; Hsu, Ku-Lung et al. (2016) Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proc Natl Acad Sci U S A 113:1086-91|
|Criado, JosÃ© R; Gilder, David A; Kalafut, Mary A et al. (2016) Cardiovascular disease risks in adult Native and MexicanÂ Americans with a history of alcohol use disorders: association with cardiovascular autonomic control. Clin Auton Res 26:87-95|
|Varodayan, Florence P; Soni, Neeraj; Bajo, Michal et al. (2016) Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala. Addict Biol 21:788-801|
|Herman, Melissa Ann; Roberto, Marisa (2016) Cell-type-specific tonic GABA signaling in the rat central amygdala is selectively altered by acute and chronic ethanol. Addict Biol 21:72-86|
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