Locally-generated acetaldehyde is involved in ethanol-mediated LTP inhibition in the hippocampus.
Consistent with the ability of severe alcohol intoxication to impair memory, high concentrations of ethanol (60mM) acutely inhibit long-term potentiation (LTP) in the CA1 region of rat hippocampal slices. To account for this, we hypothesized that local metabolism to acetaldehyde may contribute to the effects of high ethanol on synaptic function. However, sodium azide, a catalase inhibitor, and allyl sulfide, an inhibitor of cytochrome P450 2E1 (CYP2E1), failed to overcome LTP inhibition by 60mM ethanol. In contrast, LTP was successfully induced in the presence of ethanol plus 4-methylpyrazole (4MP), an inhibitor of alcohol dehydrogenase, suggesting that local metabolism via alcohol dehydrogenase contributes to synaptic effects. Furthermore, exogenously administered acetaldehyde overcame the effects of 4MP on LTP inhibition mediated by ethanol. These observations indicate that acetaldehyde generated by local metabolism within the hippocampus participates in the synaptic dysfunction associated with severe alcohol intoxication.
Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States.
Kazuhiro
K
Tokuda
Yukitoshi
Y
Izumi
Charles F
CF
Zorumski
D000079:Acetaldehyde / Q000378:metabolism* / Q000494:pharmacology; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology; D002374:Catalase / Q000037:antagonists & inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D000431:Ethanol / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D000077604:Fomepizole; D066298:In Vitro Techniques; D017774:Long-Term Potentiation; D008297:Male; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D019810:Sodium Azide / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology
D000498:Allyl Compounds; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D011720:Pyrazoles; D013440:Sulfides; D000431:Ethanol; C038491:allyl sulfide; D000077604:Fomepizole; D019810:Sodium Azide; D000426:Alcohol Dehydrogenase; D002374:Catalase; D000079:Acetaldehyde