The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of GABAA receptors, and evidence suggests that GABAergic neurosteroids are endogenous modulators of GABAA receptors and of selective effects of ethanol (EtOH). The present proposal builds on results generated in the current period of funding in the selectively bred Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) male mice. The finding that WSP mice had a persistent decrease in endogenous ALLO levels during EtOH withdrawal, in conjunction with tolerance to ALLO's anticonvulsant effect, is consistent with greater neural excitability in the WSP vs. WSR line during EtOH withdrawal. The selected line differences in the modulatory effect of ALLO on EtOH withdrawal severity likely reflects a balance between alterations in local concentration of ALLO at GABAA receptors and the concomitant change in GABAA receptor sensitivity to ALLO during EtOH withdrawal. Thus, the goals of the proposed studies are to determine the mechanism and site(s) of action underlying the tolerance to ALLO during EtOH withdrawal in WSP mice (Aim 3), the relative contribution of altered local endogenous ALLO levels (Aim 2) and altered expression of GABAA receptor subunits (Aim 4) to the line difference in ALLO sensitivity during EtOH withdrawal severity in WSP and WSR mice, and the anatomical localization and regulation of the biosynthetic enzyme 5a-reductase (Srd5a1) during EtOH withdrawal in WSP and WSR mice (Aim 1). The pattern of the results will provide essential information on whether activation of GABAA receptors in particular brain regions will be sufficient to alter EtOH withdrawal severity or sensitivity to ALLO during EtOH withdrawal as well as the critical involvement of local ALLO concentration in a specific brain region on EtOH withdrawal severity. This multidisciplinary approach will further test the hypothesis that a decrease in endogenous ALLO levels, which alters GABAergic tone, in conjunction with a decrease in GABAA receptor sensitivity, contribute to the increased withdrawal severity in WSP mice. The long-term goal of this research is to understand mechanisms underlying a genetic predisposition for increased withdrawal severity. This information will aid in our understanding of the mechanisms underlying alcohol withdrawal and will help in the development of new strategies for the treatment of alcohol dependence. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA012439-06A2
Application #
7145078
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Twombly, Dennis
Project Start
2000-03-01
Project End
2011-07-31
Budget Start
2006-08-15
Budget End
2007-07-31
Support Year
6
Fiscal Year
2006
Total Cost
$252,000
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Rossi, David J; Richardson, Ben D (2018) The Cerebellar GABAAR System as a Potential Target for Treating Alcohol Use Disorder. Handb Exp Pharmacol :
Finn, Deborah A; Jimenez, Vanessa A (2017) Dynamic Adaptation in Neurosteroid Networks in Response to Alcohol. Handb Exp Pharmacol :
Sirohi, Sunil; Richardson, Ben D; Lugo, Janelle M et al. (2017) Impact of Roux-en-Y gastric bypass surgery on appetite, alcohol intake behaviors, and midbrain ghrelin signaling in the rat. Obesity (Silver Spring) 25:1228-1236
Richardson, Ben D; Rossi, David J (2017) Recreational concentrations of alcohol enhance synaptic inhibition of cerebellar unipolar brush cells via pre- and postsynaptic mechanisms. J Neurophysiol 118:267-279
Jensen, Jeremiah P; Nipper, Michelle A; Helms, Melinda L et al. (2017) Ethanol withdrawal-induced dysregulation of neurosteroid levels in plasma, cortex, and hippocampus in genetic animal models of high and low withdrawal. Psychopharmacology (Berl) 234:2793-2811
Arguello, Amy A; Richardson, Ben D; Hall, Jacob L et al. (2017) Role of a Lateral Orbital Frontal Cortex-Basolateral Amygdala Circuit in Cue-Induced Cocaine-Seeking Behavior. Neuropsychopharmacology 42:727-735
Kaplan, Josh Steven; Nipper, Michelle A; Richardson, Ben D et al. (2016) Pharmacologically Counteracting a Phenotypic Difference in Cerebellar GABAA Receptor Response to Alcohol Prevents Excessive Alcohol Consumption in a High Alcohol-Consuming Rodent Genotype. J Neurosci 36:9019-25
Bergeson, Susan E; Nipper, Michelle A; Jensen, Jeremiah et al. (2016) Tigecycline Reduces Ethanol Intake in Dependent and Nondependent Male and Female C57BL/6J Mice. Alcohol Clin Exp Res 40:2491-2498
Guizzetti, Marina; Davies, Daryl L; Egli, Mark et al. (2016) Sex and the Lab: An Alcohol-Focused Commentary on the NIH Initiative to Balance Sex in Cell and Animal Studies. Alcohol Clin Exp Res 40:1182-91
Kaplan, Joshua S; Mohr, Claudia; Hostetler, Caroline M et al. (2016) Alcohol Suppresses Tonic GABAA Receptor Currents in Cerebellar Granule Cells in the Prairie Vole: A Neural Signature of High-Alcohol-Consuming Genotypes. Alcohol Clin Exp Res 40:1617-26

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