Chronic administration of diazepam to rats causes changes in EEG patterns and in coupling between GABA receptors and benzodiazepine binding sites in vitro.

The daily administration of diazepam (10 mg/kg i.v.) in rats elicited tolerance to the sedative effect within 2-3 days, parallel to the emerging of a stimulatory syndrome. In the EEG, the latter was accompanied by a progressive replacement of the trains of spindles with 25-30 Hz low amplitude waves. No clear signs of tolerance to the myorelaxant effect of diazepam were observed. After 10 days of treatment, the drug was discontinued. Thereafter, a single administration of diazepam elicited a stimulatory syndrome and EEG desynchronization throughout the 15 days of withdrawal. [3H]diazepam binding studies, performed in frozen-thawed membrane preparations incubated at 37 degrees C for 30 min, showed a decrease of KD values in tolerant rats up to 7 days after discontinuation of the drug. In parallel, a reduction in the ability of GABA to enhance [3H]diazepam binding, as well as to protect [3H]diazepam recognition sites from thermoinactivation at 60 degrees C, were found in tolerant rats up to 15 days after drug termination. These data suggest that a modification in the regulatory activity of GABA on benzodiazepine recognition sites might underlie the tolerance to the sedative effects and EEG changes of benzodiazepines.