The sedative but not the memory-blocking properties of ethanol are modulated by α5-subunit-containing γ-aminobutyric acid type A receptors

• Published in: Behavioural brain research Vol. 217; no. 2; pp. 379 - 385
• Main Authors: Martin, Loren J., Zurek, Agnieszka A., Bonin, Robert P., Oh, Gabriel H.T., Kim, John H., Mount, Howard T.J., Orser, Beverley A.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 01.03.2011; Elsevier
• Subjects: Acoustic Stimulation - adverse effects; Animals; Behavior, Animal; Behavioral psychophysiology; Biological and medical sciences; Cells, Cultured; Central Nervous System Depressants - pharmacology; Conditioning (Psychology) - drug effects; Conditioning (Psychology) - physiology; Dose-Response Relationship, Drug; Electric Stimulation - methods; Ethanol; Ethanol - pharmacology; Exploratory Behavior - drug effects; Fear - drug effects; Freezing Reaction, Cataleptic - drug effects; Freezing Reaction, Cataleptic - physiology; Fundamental and applied biological sciences. Psychology; GABA; Hippocampus; Hippocampus - cytology; Inhibition; Locomotion - drug effects; Locomotion - genetics; Membrane Potentials - drug effects; Membrane Potentials - genetics; Memory; Memory Disorders - chemically induced; Memory Disorders - genetics; Mice; Mice, Knockout; Patch-Clamp Techniques; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Pyramidal Cells - drug effects; Pyramidal Cells - physiology; Receptors, GABA-A - deficiency; Receptors, GABA-A - metabolism; Sedation; Time Factors; α5 subunit; α5 subunit; Ethanol; Memory; GABA; Inhibition; Sedation; Hippocampus; Central nervous system; Blocking; Subunit; Encephalon; Neurotransmitter; Biological receptor
• ISSN: 0166-4328; 1872-7549; 1872-7549
• DOI: 10.1016/j.bbr.2010.11.008

▶ Ethanol does not exert its memory-impairing effects through α5GABAA receptors. ▶ Behaviorally-relevant concentrations of ethanol do not enhance an α5GABAA receptor-mediated tonic inhibitory current in cultured hippocampal pyramidal neurons. ▶ The sedative properties of ethanol may be in part generated by ethanol's action on α5GABAA 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.