Involvement of the "peripheral" benzodiazepine receptor type (omega 3) in the tolerance to the electroencephalographic effects of benzodiazepines in rats: comparison of diazepam and clonazepam.
Rapid tolerance to the sedative effect of large doses of diazepam (10 mg/kg IV), but not of large doses of clonazepam (2 mg/kg IV) occurs in rats after 5 days of treatment on a once-a-day regimen. Electroencephalographic (EEG) studies show that such behavioral tolerance is associated with a decreased induction of spindle bursts and with an increased induction of 20-30 Hz waves (beta-like activity). Administration of clonazepam plus the agonist of the "peripheral" benzodiazepine receptor type (omega 3) Ro 5-4864 (4 mg/kg IV) for 5 days induces signs of behavioral and EEG tolerance to sedative effects of the benzodiazepine agonist. In animals treated for 5 days with diazepam plus the omega 3 antagonist PK 11195 (5 mg/kg IV), no signs of EEG and behavioral tolerance are observed. These results suggest that omega 3 type activation influences the development of rapid tolerance to the sedative effect of diazepam in rats.
Massotti
M
M
Laboratorio di Farmacologia, Istituto Superiore di Sanita, Roma, Italy.
Mele
L
L
De Luca
C
C
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002998:Clonazepam / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004361:Drug Tolerance / Q000502:physiology; D004569:Electroencephalography / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*
D001570:Benzodiazepinones; D007546:Isoquinolines; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D002998:Clonazepam; D003975:Diazepam; C037850:PK 11195