It is well known that pre-menstrual syndrome (PMS) is associated with increased ethanol consumption, which may then act to counteract premenstrual dysphoria. The purpose of this study is to examine changes in ethanol modulation of GABA function during P withdrawal, a rodent model of PMS, as a possible mechanism which may explain increased alcohol consumption during the pre-menstrual period. In addition, this paradigm will allow us to assess ethanol effects under conditions of GABA receptor subunit plasticity produced by physiologically relevant hormonal changes. For this model, animals are exposed in vivo to progesterone for three weeks and tested 24 hrs after cessation of treatment. Previous findings from this lab suggest that withdrawal from the GABA-modulatory 3aOH-5apregnan-20-one using this paradigm results in increased anxiety and seizure susceptibility due to decreases in total integrated GABA-gated current as a result of a markedly faster decay time constant for hippocampal pyramidal cells. This change in GABA current kinetics was due to significant increases in the a4 subunit of the GABA receptor. The goal of the present studies is to determine the effect of a4 subunit upregulation on ethanol effects on GABA-gated current and inhibitory synaptic currents recorded from the hippocampal slice preparation (mIPSCs and sIPSCs) correlated with a4 subunit levels using Western blot procedures. This study will test two potential mechanisms which may act to alleviate PMS-symptoms using acute and sustained ethanol treatment. It is our hypothesis that acute ethanol will increase peak GABA-gated current, while sustained ethanol administration will decrease levels of the a4 subunit in conjunction with return of GABA-gated current decay time to control levels following P withdrawal. Enhancement of GABA function by ethanol may then be reinforcing in an anxiolytic fashion to individuals suffering from PMS. Understanding the physiological changes involved in hormone-associated changes in alcohol effects may provide additional insight into potential mechanisms leading to alcohol abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012958-03
Application #
6509414
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Grandison, Lindsey
Project Start
2000-05-01
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
3
Fiscal Year
2002
Total Cost
$264,775
Indirect Cost
Name
Suny Downstate Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
068552207
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
Kuver, Aarti; Smith, Sheryl S (2016) Flumazenil decreases surface expression of ?4?2? GABAA receptors by increasing the rate of receptor internalization. Brain Res Bull 120:131-43
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Gong, Qi Hua; Smith, Sheryl S (2014) Characterization of neurosteroid effects on hyperpolarizing current at ?4?2? GABAA receptors. Psychopharmacology (Berl) 231:3525-35
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Sabaliauskas, Nicole; Shen, Hui; Homanics, Gregg E et al. (2012) Knockout of the ?-aminobutyric acid receptor subunit ?4 reduces functional ?-containing extrasynaptic receptors in hippocampal pyramidal cells at the onset of puberty. Brain Res 1450:11-23
Shen, Hui; Sabaliauskas, Nicole; Sherpa, Ang et al. (2010) A critical role for alpha4betadelta GABAA receptors in shaping learning deficits at puberty in mice. Science 327:1515-8
Zhou, Xiangping; Smith, Sheryl S (2009) Expression levels of the alpha4 subunit of the GABA(A) receptor in differentiated neuroblastoma cells are correlated with GABA-gated current. Neuropharmacology 56:1041-53

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