Effects of in vitro ethanol and fetal ethanol exposure on glutathione stimulation of N-methyl-D-aspartate receptor function.
The present studies investigated the effects of glutathione (GSH; gamma-glutamylcysteinylglycine) and its oxidized form (GSSG) on neuronal N-methyl-D-aspartate (NMDA) receptor activation in both acute and chronic preparations of ethanol exposure. It was demonstrated using fura-2-loaded dissociated brain cells from newborn rat pups that both GSH and GSSG (0-4 mM) produced concentration-dependent increases in intracellular calcium similar to those produced by NMDA and other agonists of the NMDA receptor. GSH-stimulated calcium entry was not inhibited by low intoxicating concentrations of ethanol, which contrasts with ethanol's typical inhibitory effect on NMDA-stimulated receptor activation. Behavioral studies in adult rats demonstrated that ethanol-induced sleep times were significantly decreased when 10 microliters of GSSG (20 mM) were administered intracerebroventricularly approximately 5 min before an intraperitoneal injection of 20% (w/v) ethanol (3 g/kg). These findings suggest that the less potent effect of ethanol on GSH-stimulated calcium entry as well as the reduction in ethanol-induced sleep times may be related to the presence of glycine in the peptide. The glycine found in GSH may activate the glycine site and block or reduce ethanol's action on this site. It appears that although GSH may play an important role in the activation of the NMDA receptor, this action does not involve a process that is sensitive to acute ethanol exposure. In contrast, when rat pups were chronically exposed to ethanol via prenatal exposure before the fura-2 preparation, increases in NMDA- and GSH-stimulated calcium entry were significantly decreased relative to those in pair-fed and ad libitum-fed controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Weaver
M S
MS
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78713.
Lee
Y H
YH
Morris
J L
JL
Randall
P K
PK
Schallert
T
T
Leslie
S W
SW
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D046508:Culture Techniques; D003600:Cytosol / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000503:physiopathology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D019803:Glutathione Disulfide; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D012894:Sleep Stages / Q000187:drug effects / Q000502:physiology
D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D016202:N-Methylaspartate; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide