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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (03))
Program Officer
Reilly, Matthew
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
den Hartog, Carolina R; Gilstrap, Meghin; Eaton, Bethany et al. (2017) Effects of Repeated Ethanol Exposures on NMDA Receptor Expression and Locomotor Sensitization in Mice Expressing Ethanol Resistant NMDA Receptors. Front Neurosci 11:84
Harris, R Adron; Bajo, Michal; Bell, Richard L et al. (2017) Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents. J Neurosci 37:1139-1155
Mahnke, Amanda H; Miranda, Rajesh C; Homanics, Gregg E (2017) Epigenetic mediators and consequences of excessive alcohol consumption. Alcohol 60:1-6
Skelly, M J; Ariwodola, O J; Weiner, J L (2017) Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala. Neuropharmacology 113:231-240
Rompala, Gregory R; Finegersh, Andrey; Slater, Michelle et al. (2017) Paternal preconception alcohol exposure imparts intergenerational alcohol-related behaviors to male offspring on a pure C57BL/6J background. Alcohol 60:169-177
Gilpin, N W; Weiner, J L (2017) Neurobiology of comorbid post-traumatic stress disorder and alcohol-use disorder. Genes Brain Behav 16:15-43
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
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
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
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

Showing the most recent 10 out of 60 publications