Josipa Vlainić, Maja Jazvinšćak Jembrek, Dubravka Švob Štrac, Danka Peričić
Department of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the mammalian brain, fulfills most of its physiological actions via GABA-A receptors. GABA-A receptors possess binding sites for a variety of different drugs, including clinically relevant benzodiazepines, barbiturates, general anesthetics and neurosteroides. Occupancy of these receptors by different drugs leads to regulatory changes often affecting receptor expression and/or function.
The aim of this study was to further explore the mechanisms leading to adaptive changes in GABA-A receptors following their prolonged exposure to zolpidem, a positive allosteric modulator of GABA-A receptors. Imidazopyridine zolpidem is the most widely prescribed non-benzodiazepine hypnotic, with preferential, although not exclusive, binding for receptors containing alpha1 subunit. It was suggested that drugs with high selectivity for alpha1 containing receptors produce, upon repeated treatment, less tolerance and dependence than classical benzodiazepines.
As an extension of our previous work, we treated cerebellar neuronal cells isolated from 8-days old rats with 10 microM zolpidem during 48 h. Results demonstrate that prolonged treatment of these cells with zolpidem induced changes neither in GABA-A receptor number nor in expression of alpha1 subunit mRNA. On the other hand, long-term exposure of these cells to zolpidem produced the functional uncoupling between GABA and benzodiazepine binding sites on GABA-A receptor complex as evidenced by a decreased ability of GABA to stimulate [3H]flunitrazepam binding.
We can assume that chronic zolpidem treatment might also induce tolerance if this mechanism is responsible for the development of tolerance following chronic administration of classic benzodiazepines.
Keywords: GABA-A receptors, cerebellar granulle neurons, zolpidem