DIFFERENT KINETICS OF TOLERANCE TO BEHAVIORAL AND ELECTROENCEPHALOGRAPHIC EFFECTS OF CHLORDIAZEPOXIDE IN THE RAT

The daily oral administration of chlordiazepoxide (40 mg/kg) over 9 we eks in rats elicited full tolerance to muscle relaxant effects within 7 weeks, as revealed by twice weekly evaluations of abdominal tone myo relaxation and decreased grip strength. No full tolerance was achieved , however, during the 9 weeks of treatment in terms of ataxia. Electro encephalographic (EEG) studies showed that this tolerance to the behav ioural effects was accompanied by a progressive decrease in mean power spectra, associated with a progressive decrease in the beta band, but in this case, full tolerance was reached within 4 weeks. Once weekly evaluations of the ability of chlordiazepoxide to protect the animals against pentylenetetrazole seizures revealed a similar pattern. Treatm ent with flumazenil (50 mg/kg p.o.) 24 h after the last chlordiazepoxi de administration induced a clear withdrawal syndrome associated with EEG changes which consisted of an increase in total power spectra asso ciated with an increase in the delta band (in comparison with chlordia zepoxide-dependent rats not given the antagonist). These findings sugg est that the different kinetics of the tolerance to anticonvulsant and EEG effects in comparison to myorelaxant effects can be attributed to a different involvement of benzodiazepine receptor subtypes.