Study, 1996: "Use-dependent regulation of GABAA receptors"

"Prolonged occupancy of GABAA receptors by ligands, including GABA and benzodiazepine agonists, sets in motion a series of mechanisms that can be termed use-dependent regulation. These mechanisms can be subdivided into two distinct pathways, one for GABAA receptor downregulation and another for upregulation. Treatment of cortical neurons with GABA or benzodiazepines in cultures opens the pathway for GABAA receptor downregulation, which includes (in putative temporal order): (1) desensitization (tachyphylaxis), (2) sequestration (endocytosis) of subunit polypeptides and uncoupling of allosteric interactions between GABA and benzodiazepine binding sites, (3) subunit polypeptide degradation, and (4) repression of subunit gene expression. The end-point of GABAA receptor downregulation, a reduction in receptor number, is postulated to be established initially by degradation of the receptor protein and then maintained by a diminished level of de novo synthesis."

 

"Benzodiazepine treatment of many preparations, including cells expressing recombinant GABAA receptors, may elicit only desensitization, sequestration, or uncoupling, without a decline in receptor number. Components of the GABAA receptor downregulation pathway are also evoked by chronic administration of GABAmimetics, benzodiazepines, barbiturates, and neurosteroids in animals. This downregulation correlates with the establishment of tolerance to and physical dependence on the pharmacological effects of these drugs, suggesting a cellular model for this behavior."

 

"The upregulation of GABAA receptors is observed as one of the neurotrophic actions of GABA, primarily in cultured cerebellar granule cells. Upregulation in culture is caused by enhanced expression of genes for GABAA receptor subunits and correlates with the establishment of GABAergic circuitry in the developing cerebellum. Thus, both the upregulation and downregulation of GABAA receptors appear to represent use-dependent pathways for guiding synaptic plasticity in the vertebrate central nervous system."

 

https://www.ncbi.nlm.nih.gov/pubmed/8894844 

 

 

I had to reread a few parts but overall very informative as to what is happening and not just with straight Benzos!!!!  Our poor neuro systems!!

Interesting post. Thanks for the info.

Yes, I was particularly interested in the part where it mentioned that there could be a variety of things that could happen. It says, "Benzodiazepine treatment of many preparations, including cells expressing recombinant GABAA receptors, may elicit only desensitization, sequestration, or uncoupling, without a decline in receptor number." So, you could have one, two, three or all four of those things happen.

Lapis, do you think that is possibly the difference between those who have an easier time getting off benzos vs. those of us who have a  difficult time? This is very interesting!! Thank you!!

As a layperson, yes, Terry, that's something I was thinking when I read it. I'd love to hear an expert weigh in on that.

Yes, I would too!!