Enhancing Insomnia Treatments by Modifying Drug Interactions with GABA-A Ions Channels Subunits
Background: Insomnia is a sleep disorder with 33% of adults in the general population reporting symptoms.1 Characterized by difficulties with initiating and maintaining sleep, both acute and chronic insomnia can precipitate cognitive challenges, fatigue, irritability, and increased risk of accidents.1,2 Pharmacological approaches usually target GABA-A ion channels (GABA-ARs), which are thought to balance the excitatory and inhibitory activities that regulate circadian rhythm and sleep.1
Objective: In this review, we explored the interactions between common hypnotic agents and specific subunits of the GABA-A ion channels and how this knowledge can improve future insomnia treatment.
Search Methods: I used the PubMed database and filtered through high impact journals that published relevant work between 2017-2023. I narrowed my search using the following keywords: “GABA-A ion channel”, “insomnia”, and “sleep regulation.”
Methods. Mice were injected with 3-carene from Korean pine trees and affinity 3-carene for the GABA-ARs BZ receptor was measured using radioligand binding assays.3 Molecular docking analysis of traditional Chinese hypnotic agent, Ziziphi Spinsaw Semen extract (ZSSE), was carried out to evaluate the binding affinity and conformation of the receptors to the ligands.4 Using fibroblast cells LtK-11 expressing human GABA-AR subunits from mice, manual whole cell patch-clamp experiments were administered to evaluate the potential of subunit targeting and pharmacodynamic fingerprinting.5 CRISPR-Cas9 and an adeno-associated viral (AAV) vector were used to mediate ablation in the α3 subunit in the TRN of mice and assess GABA-ARs α3 subunits’ effects on suppressing NREM sleep delta oscillation.6 Finally, extracellular tetrode recording electrodes in the prelimbic cortex and hippocampus of mice injected with Zolpidem were used to understand how common sleep agents affect NREM oscillations and neuronal activity.7
Results. 3-Carene not only showed an affinity for the GABA-ARs at the α1 and γ2 subunit, but it also increased the delay time of spontaneous inhibitory postsynaptic currents (sIPSCs) at those subunits.3 The molecular docking results showed that ZSSE increased α1 and γ2 expression in GABA-ARs in the hypothalamus and hippocampus. Thus, one of ZSSE’s mechanism to improve sleep is by increasing these subunits’ expression and inhibiting neuronal excitation.4 Seeing that CND does not feature the same sedative effects as ALZ and BRO does, which both increased current amplitudes of GABA-ARs with α1 subunit, further supports the hypothesis that α1 is highly involved in sedation and sleep.5 Recordings of the spontaneous inhibitory postsynaptic currents (sIPSCs) from TRN parvalbumin (PV) showed that α3 knockout (α3KD) led to increased delta oscillations.6 Zolpidem increased slow-wave activity (SWA), ripple activity in the hippocampus, and coupling between slow-waves and spindles. Interestingly, Zolpidem was able to increase SWA’s modulation of coordinated firing rates between the hippocampus and prefrontal cortex.7
Conclusion. GABA-A ion channel α1, α3, and γ2 subunits play an important role in sleep regulation.2,3,4,6 Stimulation of α1 and γ2 and inhibition of α3 can help avoid unwanted anxiolytic effects.5,6 Pharmacodynamic fingerprinting via subunit selectivity used to individualize insomnia therapies.6 Synchronous inhibitory activity between CA1 cells of hippocampus and prefrontal cortex are vital to improving quality and length of sleep.7
- Avidan AY, Neubauer DN. Chronic Insomnia Disorder. Continuum (Minneap Minn). 2017;23(4, Sleep Neurology):1064-1092. doi:10.1212/01.CON.0000522244.13784.bf
- Bollu PC, Kaur H. Sleep Medicine: Insomnia and Sleep. Mo Med. 2019 Jan-Feb;116(1):68-75. PMID: 30862990; PMCID: PMC6390785.
- Woo J, Yang H, Yoon M, et al. 3-carene, a phytoncide from Pine Tree has a sleep-enhancing effect by targeting the GABA-A-benzodiazepine receptors. Experimental Neurobiology. 2019;28(5):593-601. doi:10.5607/en.2019.28.5.593
- Xiao F, Shao S, Zhang H, et al. Neuroprotective effect of Ziziphi spinosae semen on rats with P-chlorophenylalanine-induced insomnia via activation of Gabaa receptor. Frontiers in Pharmacology. 2022;13. doi:10.3389/fphar.2022.965308
- Fernandes H, Batalha V, Braksator E, et al. Voltage-clamp evidence of Gabaa receptor subunit-specific effects: Pharmacodynamic fingerprint of chlornordiazepam, the major active metabolite of mexazolam, as compared to alprazolam, bromazepam, and Zolpidem. Pharmacological Reports. 2022;74(5):956-968. doi:10.1007/s43440-022-00411-x
- Uygun DS, Yang C, Tilli ER, et al. Knockdown of Gabaa alpha3 subunits on thalamic reticular neurons enhances deep sleep in mice. Nature Communications. 2022;13(1). doi:10.1038/s41467-022-29852-x
- Kersanté F, Purple RJ, Jones MW. The GABAA receptor modulator zolpidem augments hippocampal-prefrontal coupling during non-REM sleep. Neuropsychopharmacology. 2022;48(4):594-604. doi:10.1038/s41386-022-01355-9