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Single Ethanol Withdrawal Regulates Extrasynaptic δ-GABAA Receptors Via PKCδ Activation
1Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, China.
Frontiers in Molecular Neuroscience
|May 15, 2018
Summary
Alcohol withdrawal rapidly alters brain function by affecting GABA-A receptors (GABAARs). Protein kinase C delta (PKCδ) plays a key role in regulating these changes, impacting receptor levels and function.
Area of Science:
- Neuroscience
- Neuropharmacology
- Molecular Biology
Background:
- Alcohol (ethanol, EtOH) is a widely abused drug impacting brain function, with GABA-A receptors (GABAARs) as primary targets.
- Plastic changes in GABAARs following alcohol withdrawal are linked to addiction, tolerance, and withdrawal symptoms.
- Mechanisms regulating GABAAR abundance and localization during alcohol exposure and withdrawal remain unclear, particularly concerning extrasynaptic δ-GABAARs.
Purpose of the Study:
- To investigate the mechanisms behind the rapid regulation of extrasynaptic δ-GABAARs after a single alcohol withdrawal episode.
- To elucidate the role of protein kinase C (PKC) signaling pathways in alcohol-induced GABAAR plasticity.
Main Methods:
- Cultured rat hippocampal neurons were used to study the effects of acute alcohol exposure and subsequent withdrawal.
- Measurements included extrasynaptic tonic current (Itonic) amplitude and responsiveness to acute alcohol.
- Pharmacological manipulations involved okadaic acid (OA), phorbol 12,13-dibutyrate (PDBu), PKC inhibition, and specific PKCδ inhibition.
Main Results:
- Acute alcohol exposure increased tonic current, while withdrawal reduced both tonic current and alcohol responsiveness.
- PKC inhibition prevented alcohol withdrawal-induced reductions in tonic current, alcohol tolerance, and δ-GABAAR subunit levels.
- Alcohol withdrawal increased PKCδ levels, and PKCδ inhibition reversed alcohol-induced alterations in δ-GABAAR levels and function.
Conclusions:
- A single alcohol withdrawal episode rapidly alters extrasynaptic δ-GABAAR function and abundance in hippocampal neurons.
- Protein kinase C delta (PKCδ) is critically involved in mediating these rapid, alcohol withdrawal-induced changes in δ-GABAARs.
- These findings highlight PKCδ as a key regulator of alcohol-induced neuroplasticity relevant to addiction and withdrawal.
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