Restoration of GABAA Receptor Function after Benzodiazepine Use: A Meta-Analysis (2020)
Posted: Sun Oct 25, 2020 11:21 pm
Title: Restoration of GABAA Receptor Function after Benzodiazepine Use: A Meta-Analysis (2020)
Abstract:
"Muscimol (MML) is a psychoactive compound derived from the mushroom Amanita muscaria [62]. MML exhibits depressant, sedative-hypnotic and hallucinogenic activity after purification. MML acts as a GABAA agonist by selectively binding to the δ subunit on the GABA binding site, distinguishing it from most other GABAA PAMs. Muscimol demonstrates excellent therapeutic effects but must be monitored closely in humans due to lack of research and potential risks in patients withdrawing from BZD [63]." ...
"Two potential medications that may restore GABAA receptor function are the gabapentinoids (Figure 5) and muscimol (MML) (Figure 14). Since gabapentinoids increase extrasynaptic GABA levels and block Ca2+ channel activity, more GABA is available to bind to extrasynaptic receptors. Because gabapentinoids also block excitatory Ca2+ channel activity, they inhibit glutamate release and prevent NMDA/AMPA receptor activation. Since NMDA/AMPA receptors become upregulated during BZD withdrawal, less glutamate prevents this upregulation [42]. Therefore, the gabapentinoids may serve an important role in BZD dependence. MML also exhibits promising properties. Research has shown that MML is potent GABAA agonist and binds directly to the δ subunit on the GABA binding site [63]. Stimulating the δ subunit is unique for MML since none of our other medications activated this isoform. In addition, MML is not an allosteric modulator and does not induce tolerance like the BZDs, yet interestingly produces similar effects [63]. If gabapentinoids and MML were used together, their pharmacology may benefit GABAA conformation normalization. Since MML is a GABAA agonist and gabapentinoids increase extrasynaptic GABA levels, their combined actions may alleviate withdrawal symptoms. Increased GABA concentrations and a GABAA agonist may stimulate the GABAA receptor enough to allow its gating structure to return to its normal state. Thus, our hypothesis supports the NMDA/AMPA and GABAA uncoupling models and rejects the receptor down regulation theory."
Authors: Warlick, H. G., De Souza, G. N., & Gallicchio, V. S. (2020) Restoration of GABAA Receptor Function after Benzodiazepine Use: A Meta-Analysis.
Link (Currently broken): https://www.genesispub.org/wp-content/u ... alysis.pdf
Abstract:
"Muscimol (MML) is a psychoactive compound derived from the mushroom Amanita muscaria [62]. MML exhibits depressant, sedative-hypnotic and hallucinogenic activity after purification. MML acts as a GABAA agonist by selectively binding to the δ subunit on the GABA binding site, distinguishing it from most other GABAA PAMs. Muscimol demonstrates excellent therapeutic effects but must be monitored closely in humans due to lack of research and potential risks in patients withdrawing from BZD [63]." ...
"Two potential medications that may restore GABAA receptor function are the gabapentinoids (Figure 5) and muscimol (MML) (Figure 14). Since gabapentinoids increase extrasynaptic GABA levels and block Ca2+ channel activity, more GABA is available to bind to extrasynaptic receptors. Because gabapentinoids also block excitatory Ca2+ channel activity, they inhibit glutamate release and prevent NMDA/AMPA receptor activation. Since NMDA/AMPA receptors become upregulated during BZD withdrawal, less glutamate prevents this upregulation [42]. Therefore, the gabapentinoids may serve an important role in BZD dependence. MML also exhibits promising properties. Research has shown that MML is potent GABAA agonist and binds directly to the δ subunit on the GABA binding site [63]. Stimulating the δ subunit is unique for MML since none of our other medications activated this isoform. In addition, MML is not an allosteric modulator and does not induce tolerance like the BZDs, yet interestingly produces similar effects [63]. If gabapentinoids and MML were used together, their pharmacology may benefit GABAA conformation normalization. Since MML is a GABAA agonist and gabapentinoids increase extrasynaptic GABA levels, their combined actions may alleviate withdrawal symptoms. Increased GABA concentrations and a GABAA agonist may stimulate the GABAA receptor enough to allow its gating structure to return to its normal state. Thus, our hypothesis supports the NMDA/AMPA and GABAA uncoupling models and rejects the receptor down regulation theory."
Authors: Warlick, H. G., De Souza, G. N., & Gallicchio, V. S. (2020) Restoration of GABAA Receptor Function after Benzodiazepine Use: A Meta-Analysis.
Link (Currently broken): https://www.genesispub.org/wp-content/u ... alysis.pdf