Locally-generated Acetaldehyde Contributes to the Effects of Ethanol on Neurosteroids and LTP in the Hippocampus.
BACKGROUND
As severe alcohol intoxication impairs memory function, a high concentration of ethanol (60 mM) acutely inhibits long-term potentiation (LTP), a cellular model of learning and memory, in rat hippocampal slices. Neurosteroids are involved in this LTP inhibition. We recently reported that the inhibitory effects of 60 mM ethanol are blocked by 4-methylpyrazole (4MP), an inhibitor of alcohol dehydrogenase, suggesting that acetaldehyde locally generated within the hippocampus participates in LTP inhibition.


OBJECTIVE
We investigated whether acetaldehyde generated by ethanol metabolism contributes to neurosteroidogenesis and LTP inhibition.


RESULTS
Like 60 mM ethanol, we found that exogenous acetaldehyde enhanced neurosteroid immunostaining in CA1 pyramidal neurons, and that augmented neurosteroid immunostaining by high ethanol alone was blocked by 4MP but not by inhibitors of other ethanol metabolism pathways. The inhibitory effects of 60 mM ethanol on LTP were mimicked by a lower concentration of ethanol (20 mM) plus acetaldehyde (60 μM), although neither agent alone was effective at these concentrations, suggesting that 60 mM ethanol inhibits LTP via multiple actions, one of which involves acetaldehyde and the other of which requires only 20 mM ethanol. The effects of ethanol and acetaldehyde on neurosteroid staining and LTP were overcome by inhibition of neurosteroid synthesis and by blockade of N-methyl-D-aspartate receptors (NMDARs).


CONCLUSIONS
These observations indicate that acetaldehyde generated by local ethanol metabolism within the hippocampus serves as a signal for neurosteroid synthesis in pyramidal neurons, and 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.
Kazuhiro
K
Tokuda
Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110 ; The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110.
Yukitoshi
Y
Izumi
Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110 ; Department of Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110 ; The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, 660 South Euclid Avenue St. Louis, MO 63110.
Charles F
CF
Zorumski
Class III ADH; allopregnanolone; binge drinking; blackout; finasteride; hangover