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 weeks in rats elicited full tolerance to muscle relaxant effects within 7 weeks, as revealed by twice weekly evaluations of abdominal tone myorelaxation and decreased grip strength. No full tolerance was achieved, however, during the 9 weeks of treatment in terms of ataxia. Electroencephalographic (EEG) studies showed that this tolerance to the behavioural 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. Treatment with flumazenil (50 mg/kg p.o.) 24 h after the last chlordiazepoxide administration induced a clear withdrawal syndrome associated with EEG changes which consisted of an increase in total power spectra associated with an increase in the delta band (in comparison with chlordiazepoxide-dependent rats not given the antagonist). These findings suggest 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.
Sala
M
M
Institute of Pharmacology, Faculty of Mathematical, Physical and Natural Sciences, University of Milan, Italy.
Leone
M P
MP
Lampugnani
P
P
Braida
D
D
Gori
E
E
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002707:Chlordiazepoxide / Q000494:pharmacology*; D004361:Drug Tolerance; D004569:Electroencephalography / Q000187:drug effects*; D007700:Kinetics; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D000927:Anticonvulsants; D002707:Chlordiazepoxide