Study, Jun/18: "Diazepam-induced loss of inhibitory synapses mediated by..."

The full title of this English study is "ηηDiazepam-induced loss of inhibitory synapses mediated by PLCδ/ Ca 2+ /calcineurin signalling downstream of GABAA receptors".

https://www.ncbi.nlm.nih.gov/pubmed/29904150

Molecular Psychiatry: 2018 Jun 14. doi: 10.1038/s41380-018-0100-y. [Epub ahead of print]

ηηDiazepam-induced loss of inhibitory synapses mediated by PLCδ/ Ca 2+ /calcineurin signalling downstream of GABAA receptors.

Nicholson MW1, Sweeney A1, Pekle E1, Alam S1, Ali AB1, Duchen M2, Jovanovic JN3.

Author information

1

    UCL School of Pharmacy, University College London, London, WC1N 1AX, UK.

2

    Neuroscience, Physiology and Pharmacology, University College London, WC1E 6BT, London, UK.

3

    UCL School of Pharmacy, University College London, London, WC1N 1AX, UK. j.jovanovic@ucl.ac.uk.

Abstract

Benzodiazepines facilitate the inhibitory actions of GABA by binding to γ-aminobutyric acid type A receptors (GABAARs), GABA-gated chloride/bicarbonate channels, which are the key mediators of transmission at inhibitory synapses in the brain. This activity underpins potent anxiolytic, anticonvulsant and hypnotic effects of benzodiazepines in patients. However, extended benzodiazepine treatments lead to development of tolerance, a process which, despite its important therapeutic implications, remains poorly characterised. Here we report that prolonged exposure to diazepam, the most widely used benzodiazepine in clinic, leads to a gradual disruption of neuronal inhibitory GABAergic synapses. The loss of synapses and the preceding, time- and dose-dependent decrease in surface levels of GABAARs, mediated by dynamin-dependent internalisation, were blocked by Ro 15-1788, a competitive benzodiazepine antagonist, and bicuculline, a competitive GABA antagonist, indicating that prolonged enhancement of GABAAR activity by diazepam is integral to the underlying molecular mechanism. Characterisation of this mechanism has revealed a metabotropic-type signalling downstream of GABAARs, involving mobilisation of Ca2+ from the intracellular stores and activation of the Ca2+/calmodulin-dependent phosphatase calcineurin, which, in turn, dephosphorylates GABAARs and promotes their endocytosis, leading to disassembly of inhibitory synapses. Furthermore, functional coupling between GABAARs and Ca2+ stores was sensitive to phospholipase C (PLC) inhibition by U73122, and regulated by PLCδ, a PLC isoform found in direct association with GABAARs. Thus, a PLCδ/Ca2+/calcineurin signalling cascade converts the initial enhancement of GABAARs by benzodiazepines to a long-term downregulation of GABAergic synapses, this potentially underpinning the development of pharmacological and behavioural tolerance to these widely prescribed drugs.

I'm not understanding this.

My guess is that the more research done, the more the scientists will realize what terrible drugs benzos are in general and scratch their heads, wondering why they are prescribed so freely with all the havoc on sensitive receptors they cause.

Can you explain some of it to me?

Hi Terry,

I'm hoping one of our resident science-type folks will jump in here to explain the details! It's yet more evidence of downregulation of the GABA receptors.

Yes, more evidence of downregulation of GABAaRs via disturbances in intracellular processes and intracellular trafficking.

Quote

....which, in turn, dephosphorylates GABAARs and promotes their endocytosis, leading to disassembly of inhibitory synapses.

.....Thus, a PLCδ/Ca2+/calcineurin signalling cascade converts the initial enhancement of GABAARs by benzodiazepines to a long-term downregulation of GABAergic synapses, this potentially underpinning the development of pharmacological and behavioural tolerance to these widely prescribed drugs.

End quote