Molecular mechanisms involved in benzodiazepine tolerance

FERRERI, MC; GUTIERREZ, ML; GRAVIELLE, MC

Congreso; Congreso SAN 2013; 2013

Chronic treatment with benzodiazepines produces tolerance to their pharmacological effects. Tolerance to the sedative effects in rats occurs after a 7 day-treatment with diazepam (15 mg/kg, subcutaneous injections) whereas tolerance to the anxiolytic effects develops after a 14 day-treatment, suggesting different mechanisms. The aim of this work was to study the molecular mechanism of tolerance to benzodiazepines. Chronic diazepam administration during 7 and 14 days in rats (Sprague-Dawley) induced a decrease in the potentiation of [3H] flunitrazepam binding by GABA, named uncoupling. It has been previously reported that chronic benzodiazepine administration produces selective alterations in the levels of GABAA receptor subunits, without changes in the number of receptors. In order to investigate whether tolerance is mediated by a change in the receptor subunit composition, we performed receptor immunoprecitation experiments followed by western blot assays. Results from these experiments showed that diazepam administration during 14, but not 7 days, induced an increase in the percentage of alfa1/gamma2 receptors. In conclusion, our results suggest that tolerance to the sedative and anxiolytic effects of benzodiazepines is associated with an uncoupling of GABA and benzodiazepine sites. Tolerance to the anxiolytic actions of benzodiazepines is also accompanied by a change in receptor subunit combination.