This proposal is the second submission of a competing renewal to continue our investigations into the neurobiological basis for sex differences in ethanol dependence and withdrawal. To date, we have identified important differences between male and female rats in adaptations of GABA-A and NMDA receptors during ethanol dependence and early withdrawal across several brain sites. We recently found significant and robust behavioral sex differences in the timing for recovery from ethanol withdrawal. Whereas both males and females showed significant withdrawal signs at 24 hr, females, but not males, appeared to have recovered by 3 days. Therefore, the overall goal of this project is to elucidate the mechanistic underpinnings for behavioral expressions of ethanol withdrawal at 24 hr and 3 days. We hypothesize that differences in recovery from ethanol withdrawal involve sex-selective changes in GABAergic and glutamatergic neurotransmission that occur as a result of the differing hormonal milieu between males and females. To test this hypothesis we will compare and contrast findings in young adult male, cycling diestrus female and ovariectomized female rats. The proposed studies will allow us to delineate the importance of hormonal modulation in conferring sex differences in recovery from ethanol withdrawal. This project will test the hypothesis by these aims: 1. assessment of several ethanol withdrawal behaviors, including responses to drug treatments, at early (24 hr) and later (3 days) withdrawal, 2. identification of concomitant sex differences in brain activation with analysis of modulation of GABA-A and NMDA receptors at these same times of withdrawal, and 3. analysis of ethanol withdrawal-induced changes in GABA, glutamate and steroid levels. We expect to find that the differing hormonal milieu between males and cycling females regulates adaptations of GABAergic and glutamatergic neurotransmission that confers recovery from ethanol withdrawal. Findings resulting from these proposed studies should show that inherent, neurobiological regulation due to hormonal status is an important factor influencing actions of ethanol, with adaptations being different for recovery than development of dependence. Increasing our understanding of sex-selective mechanism underlying withdrawal should help guide us towards improving treatments for alcohol withdrawal in both women and men.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011877-10
Application #
7695545
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (05))
Program Officer
Cui, Changhai
Project Start
1999-09-27
Project End
2011-12-31
Budget Start
2009-09-01
Budget End
2011-12-31
Support Year
10
Fiscal Year
2009
Total Cost
$273,947
Indirect Cost
Name
University of Maine Orono
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
186875787
City
Orono
State
ME
Country
United States
Zip Code
04469
Walls, Shawn A; Rosenwasser, Alan M; Devaud, Leslie L (2013) Sex and regional differences in effects of chronic intermittent ethanol exposure on subsequent excitotoxic challenges in hippocampal slice cultures. Neurosci Lett 550:6-11
Devaud, Leslie L; Walls, Shawn A; McCulley 3rd, Walter D et al. (2012) Voluntary wheel running attenuates ethanol withdrawal-induced increases in seizure susceptibility in male and female rats. Pharmacol Biochem Behav 103:18-25
Walls, Shawn A; Macklin, Zachary L; Devaud, Leslie L (2012) Ethanol-induced loss-of-righting response during ethanol withdrawal in male and female rats: associations with alterations in Arc labeling. Alcohol Clin Exp Res 36:234-41
McCulley 3rd, Walter D; Walls, Shawn A; Khurana, Ritu C et al. (2012) Running wheel activity protects against increased seizure susceptibility in ethanol withdrawn male rats. Pharmacol Biochem Behav 100:485-9
Darvesh, Altaf S; Carroll, Richard T; Geldenhuys, Werner J et al. (2011) In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery. Expert Opin Drug Discov 6:109-127
Reilly, William; Koirala, Bikul; Devaud, Leslie L (2009) Sex differences in acoustic startle responses and seizure thresholds between ethanol-withdrawn male and female rats. Alcohol Alcohol 44:561-6
Alele, P E; Devaud, L L (2007) Sex differences in steroid modulation of ethanol withdrawal in male and female rats. J Pharmacol Exp Ther 320:427-36