The sedative but not the memory-blocking properties of ethanol are modulated by α5-subunit-containing γ-aminobutyric acid type A receptors.
The precise mechanisms underlying the memory-blocking properties of ethanol are unknown, in part because ethanol targets a wide array of neurotransmitter receptors and transporters. The aim of this study was to determine whether the memory loss caused by ethanol is mediated, in part, by α5 subunit-containing γ-aminobutyric acid subtype A receptors. These receptors have been implicated in learning and memory processes and are targets for a variety of neurodepressive drugs. Also, since these receptors generate a tonic inhibitory current in hippocampal pyramidal neurons, we examined whether concentrations of ethanol that block memory in vivo increased the tonic current using whole-cell patch-clamp recordings in hippocampal neurons. Null mutant mice lacking the α5 subunit (Gabra5-/-) and wild-type mice were equally impaired in contextual fear conditioning by moderate (1mg/kg) and high (1.5mg/kg) doses of ethanol. The higher dose of ethanol also reduced auditory delay fear conditioning to the same extent in the two genotypes. Interestingly, wild-type mice were more sensitive than Gabra5-/- mice to the sedative effects of low (0.5mg/kg) and moderate (1mg/kg) doses of ethanol in the open-field task. Concentrations of ethanol that impaired memory performance in vivo did not increase the amplitude of the tonic current. Together, the results suggest that the α5-subunit containing γ-aminobutyric acid subtype A receptors are not direct targets for positive modulation by ethanol nor do they contribute to ethanol-induced memory loss. In contrast, these receptors may contribute to the sedative properties of ethanol.
Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Loren J
LJ
Martin
Agnieszka A
AA
Zurek
Robert P
RP
Bonin
Gabriel H T
GH
Oh
John H
JH
Kim
Howard T J
HT
Mount
Beverley A
BA
Orser
D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D000431:Ethanol / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000187:drug effects*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008569:Memory Disorders / Q000139:chemically induced* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000172:deficiency / Q000378:metabolism*; D013997:Time Factors
D002492:Central Nervous System Depressants; C496250:Gabra5 protein, mouse; D011963:Receptors, GABA-A; D000431:Ethanol