Naslov
The effects of prolonged exposure of recombinant α1β2γ2S GABA-A receptors to benzodiazepines

Autori
Švob Štrac, Dubravka

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, neobjavljeni rad, znanstveni

Skup
CSHL/FENS Summer course "Cellular biology of addiction"

Mjesto i datum
Barcelona, Španjolska, 18.08.2012. - 25.08.2012

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
benzodiazepines; GABA-A receptor; prolonged exposure; tolerance and dependence

Sažetak
Prolonged exposure to benzodiazepines, drugs known to produce tolerance and dependence and to be abused, leads to adaptive changes in GABA-A receptors. To further explore underlying mechanisms, we studied the effects of prolonged benzodiazepine treatment on the recombinant α1β2γ2S GABA-A receptors stably expressed in HEK 293 cells. Long-term exposure of these cells to benzodiazepines increased the number of binding sites for GABA, benzodiazepines and convulsants, suggesting the enhancement the overall GABA-A receptors number. Difference in the number of GABA binding sites on cell surface between control and treated intact cells suggested that benzodiazepine drugs up-regulate functionally relevant receptors. A general trophic effect of these drugs could be excluded since they did not affect cell proliferation and viability. Experiments with actinomycin D and cycloheximide, the inhibitors of RNA and protein synthesis, suggested increased de novo synthesis of receptor subunits at transcriptional and translational level. These findings were confirmed by results demonstrating up-regulation of the α1 subunit mRNA, and β2 and γ2 subunit proteins following prolonged exposure to these drugs. 24 h after the discontinuation of long-term benzodiazepine treatment, the number of GABA-A receptor binding sites returned to control levels. In addiction, prolonged benzodiazepine administration produced a decrease in the allosteric functional coupling between benzodiazepine and GABA binding sites.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA