Ethanol (EtOH) is abused for both its positive and negative reinforcing effects. Although much is known about the neurobiological substrates underlying EtOH's positive reinforcing effects, relatively little is known about the neurophysiological mechanisms and brain regions that contribute to EtOH's negative reinforcing properties. In this proposal, we take advantage of a genetically engineered mouse line that exhibits increased sensitivity to some of EtOH's negative reinforcing effects. We previously demonstrated that these GABAA receptor alpha1 subunit gene knockin mice exhibit an increase in several measures of acute EtOH-induced anxiolysis and marked increases in EtOH withdrawal seizures. The experiments proposed will integrate neurobiological and behavioral approaches, in global and brain region specific knockin mice, to dissect the mechanisms through which chronic EtOH exposure and withdrawal lead to functional deficits in GABAergic synaptic inhibition.
These aims will address the hypothesis that EtOH-induced GABAergic synaptic adaptation in the hippocampus and basolateral amygdala lead to brain-region specific alterations in anxiety-like behavior, withdrawal seizures, and dependence-induced escalations in EtOH drinking. On a more basic level, EtOH alters gene expression. Undoubtedly such EtOH- induced neuroadaptations are also intimately involved in the long-term effects of EtOH on the brain. This is especially true for the transition from recreational drinking to EtOH abuse and alcoholism;the brains of alcoholics have a transcriptome that differs from non-alcoholics. While numerous studies have catalogued changes in EtOH-induced gene expression, a very basic and profound question has not yet been addressed. What is the mechanism by which EtOH reprograms the brain transcriptome? We hypothesize that EtOH-induced epigenetic changes are the fundamental mechanism responsible for this important effect of EtOH. Thus, the final aim will investigate the epigenetic effects of EtOH.

Public Health Relevance

Relevance EtOH addiction remains an imposing medical and socio-economic concern for our society. Elucidating the molecular and neurophysiological substrates that underlie EtOH addiction will facilitate the development of more effective treatment strategies for alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA010422-16
Application #
8270520
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (03))
Program Officer
Reilly, Matthew
Project Start
1995-08-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
16
Fiscal Year
2012
Total Cost
$429,671
Indirect Cost
$80,425
Name
University of Pittsburgh
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Skelly, M J; Chappell, A M; Ariwodola, O J et al. (2016) Behavioral and neurophysiological evidence that lateral paracapsular GABAergic synapses in the basolateral amygdala contribute to the acquisition and extinction of fear learning. Neurobiol Learn Mem 127:10-6
Rompala, Gregory R; Finegersh, Andrey; Slater, Michelle et al. (2016) Paternal preconception alcohol exposure imparts intergenerational alcohol-related behaviors to male offspring on a pure C57BL/6J background. Alcohol :
Finegersh, Andrey; Homanics, Gregg E (2016) Chromatin immunoprecipitation and gene expression analysis of neuronal subtypes after fluorescence activated cell sorting. J Neurosci Methods 263:81-8
Rompala, Gregory R; Finegersh, Andrey; Homanics, Gregg E (2016) Paternal preconception ethanol exposure blunts hypothalamic-pituitary-adrenal axis responsivity and stress-induced excessive fluid intake in male mice. Alcohol 53:19-25
Stetler, R Anne; Gao, Yanqin; Leak, Rehana K et al. (2016) APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury. Proc Natl Acad Sci U S A 113:E3558-67
Cai, Xiaoyun; Huang, Huizhen; Kuzirian, Marissa S et al. (2016) Generation of a KOR-Cre knockin mouse strain to study cells involved in kappa opioid signaling. Genesis 54:29-37
Skelly, M J; Chappell, A E; Carter, E et al. (2015) Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: Possible role of disrupted noradrenergic signaling. Neuropharmacology 97:149-59
Rau, Andrew R; Ariwodola, Olusegun J; Weiner, Jeff L (2015) Postsynaptic adenosine A2A receptors modulate intrinsic excitability of pyramidal cells in the rat basolateral amygdala. Int J Neuropsychopharmacol 18:
Naito, A; Muchhala, K H; Trang, J et al. (2015) Manipulations of extracellular Loop 2 in α1 GlyR ultra-sensitive ethanol receptors (USERs) enhance receptor sensitivity to isoflurane, ethanol, and lidocaine, but not propofol. Neuroscience 297:68-77
Finegersh, Andrey; Rompala, Gregory R; Martin, David I K et al. (2015) Drinking beyond a lifetime: New and emerging insights into paternal alcohol exposure on subsequent generations. Alcohol 49:461-70

Showing the most recent 10 out of 45 publications