This competing continuation project will continue to examine the effects of acute and chronic ethanol administration on calcium entry into neuronal preparations. The focus of the experiments will be to study the effects of ethanol on NMDA-stimulated calcium entry into dissociated brain cells. Studies will also be conducted on dihydropyridine-(L-type) and w-conotoxin- sensitive (N and L type) calcium channels and their interactions with NMDA receptors. NMDA-stimulated glutamate receptors in the brain appear to be involved in many important processes such as neuronal development, neuronal toxicity and learning and memory. Recent studies in our and other laboratories have shown that NMDA receptor-mediated processes in the brain are highly sensitive to inhibition by ethanol. The studies described in this application will characterize the sensitivity of NMDA-stimulated calcium entry into dissociated brain cells from brain regions known to have high, intermediate and low densities of NMDA receptors. Furthermore, mechanisms of ethanol's inhibitory effects on the NMDA receptor will be determined by studying the role of key modulatory sites (glycine co-agonist site, PCP-inhibitory site, Mg++ inhibitory site and the competitive receptor site) in activating NMDA function (by studying calcium entry) and receptor binding in the presence and absence of ethanol. Recent evidence suggests that there may be links between neuronal abnormalities associated with fetal alcohol exposure and alterations in number or function of NMDA receptors; thus, studies will be conducted to examine the effects of fetal alcohol exposure on NMDA-stimulated calcium entry into isolated dissociated neurons. Receptor binding studies will also be conducted on brain membranes isolated from fetal alcohol exposed rat pups to study its influence on NMDA-receptor modulation. Finally, studies will be conducted to examine the effects of chronic ethanol exposure in adult rats on NMDA- receptor modulation.

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 #
5R37AA005809-18
Application #
2855739
Study Section
Special Emphasis Panel (NSS)
Project Start
1982-07-01
Project End
2001-12-31
Budget Start
1999-01-01
Budget End
2001-12-31
Support Year
18
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Neurosciences
Type
Schools of Pharmacy
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
Morrow, A Leslie; Ferrani-Kile, Karima; Davis, Margaret I et al. (2004) Ethanol effects on cell signaling mechanisms. Alcohol Clin Exp Res 28:217-27
Nixon, Kimberly; Hughes, Peter D; Amsel, Abram et al. (2004) NMDA receptor subunit expression after combined prenatal and postnatal exposure to ethanol. Alcohol Clin Exp Res 28:105-12
Ferrani-Kile, K; Randall, P K; Leslie, S W (2003) Acute ethanol affects phosphorylation state of the NMDA receptor complex: implication of tyrosine phosphatases and protein kinase A. Brain Res Mol Brain Res 115:78-86
Brownson, Delia M; Mabry, Tom J; Leslie, Steven W (2002) The cycad neurotoxic amino acid, beta-N-methylamino-L-alanine (BMAA), elevates intracellular calcium levels in dissociated rat brain cells. J Ethnopharmacol 82:159-67
Nixon, Kimberly; Hughes, Peter D; Amsel, Abram et al. (2002) NMDA receptor subunit expression following early postnatal exposure to ethanol. Brain Res Dev Brain Res 139:295-9
Acquaah-Mensah, George K; Kehrer, James P; Leslie, Steven W (2002) In utero ethanol suppresses cerebellar activator protein-1 and nuclear factor-kappa B transcriptional activation in a rat fetal alcohol syndrome model. J Pharmacol Exp Ther 301:277-83
Hughes, P D; Wilson, W R; Leslie, S W (2001) Effect of gestational ethanol exposure on the NMDA receptor complex in rat forebrain: from gene transcription to cell surface. Brain Res Dev Brain Res 129:135-45
Acquaah-Mensah, G K; Leslie, S W; Kehrer, J P (2001) Acute exposure of cerebellar granule neurons to ethanol suppresses stress-activated protein kinase-1 and concomitantly induces AP-1. Toxicol Appl Pharmacol 175:10-8
Hughes, P D; Kim, Y N; Randall, P K et al. (1998) Effect of prenatal ethanol exposure on the developmental profile of the NMDA receptor subunits in rat forebrain and hippocampus. Alcohol Clin Exp Res 22:1255-61
Diaz-Granados, J L; Spuhler-Phillips, K; Lilliquist, M W et al. (1997) Effects of prenatal and early postnatal ethanol exposure on [3H]MK-801 binding in rat cortex and hippocampus. Alcohol Clin Exp Res 21:874-81

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