1. High ethanol preference and dissociated memory are co-occurring phenotypes associated with hippocampal GABA A R-δ receptor levels.
- Author
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Jovasevic V and Radulovic J
- Subjects
- Amnesia physiopathology, Animals, Behavior, Animal drug effects, Behavior, Animal physiology, Choice Behavior drug effects, Conditioning, Classical drug effects, Conditioning, Classical physiology, Fear, GABA Agonists pharmacology, Hippocampus physiopathology, Isoxazoles pharmacology, Mammillary Bodies metabolism, Mammillary Bodies physiopathology, Memory drug effects, Memory, Episodic, Mice, MicroRNAs drug effects, MicroRNAs metabolism, Neural Inhibition, Neural Pathways, Neurons drug effects, Neurons metabolism, Neurons physiology, Pyramidal Cells drug effects, Pyramidal Cells physiology, RNA, Messenger drug effects, RNA, Messenger metabolism, Receptors, GABA-A drug effects, Amnesia metabolism, Central Nervous System Depressants administration & dosage, Choice Behavior physiology, Ethanol administration & dosage, Hippocampus metabolism, Memory physiology, Pyramidal Cells metabolism, Receptors, GABA-A metabolism
- Abstract
Alcohol use disorder (AUD) frequently co-occurs with dissociative disorders and disorders with dissociative symptoms, suggesting a common neurobiological basis. It has been proposed that facilitated information processing under the influence of alcohol, resulting in the formation of dissociated memories, might be an important factor controlling alcohol use. Access to such memories is facilitated under the effect of alcohol, thus further reinforcing alcohol use. To interrogate possible mechanisms associated with these phenotypes, we used a mouse model of dissociative amnesia, combined with a high-alcohol preferring (HAP) model of AUD. Dissociated memory was induced by activation of hippocampal extrasynaptic GABA type A receptor delta subunits (GABA
A R-δ), which control tonic inhibition and to which ethanol binds with high affinity. Increased ethanol preference was associated with increased propensity to form dissociated memories dependent on GABAA R-δ in the dorsal hippocampus (DH). Furthermore, the DH level of GABAA R-δ protein, but not mRNA, was increased in HAP mice, and was inversely correlated to the level of miR-365-3p, suggesting an miRNA-mediated post-transcriptional mechanism contributing to elevated GABAA R-δ. The observed changes of DH GABAA R-δ were associated with a severe reduction of excitatory projections stemming from GABAA R-δ-containing pyramidal neurons in the subiculum and terminating in the mammillary body. These results suggest that both molecular and circuit dysfunction involving hippocampal GABAA R-δ receptors might contribute to the co-occurrence of ethanol preference and dissociated information processing., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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