Male ICR mice (20-35 g) were given either 5-(2-cyclohexylideneethyl)-5-ethyl
barbituric acid (
CHEB) alone (10-15 mg/kg i.p.) or
CHEB (25-75 mg/kg i.p.) after a 1 h pretreatment with
phenobarbital (75 mg/kg i.p.).
CHEB alone (10 mg/kg) produced excitatory behavior but not convulsive
seizures. Higher doses (11-15 mg/kg) produced convulsive
seizures resulting in death. Pretreatment with
phenobarbital prevented seizure activity. Following
phenobarbital pretreatment,
CHEB in doses of 50 and 75, but not 25 mg/kg, resulted in
hypnosis of 53 +/- 16 and 64 +/- 9 min duration, respectively. In vitro,
CHEB (10-200 microM) significantly inhibited 'fast-phase' (3 s) K+-stimulated 45Ca2+ uptake into cerebrocortical synaptosomes.
CHEB (10 and 100 microM) also significantly increased basal 45Ca2+ uptake. The addition of
CHEB (50 and 100 microM) or
pentobarbital (100 microM) to striatal synaptosomes inhibited 'fast-phase' K+-stimulated 45Ca2+ uptake and endogenous
dopamine release.
CHEB (10-200 microM), but not
pentobarbital (100 microM), produced a time- and dose-dependent increase in the resting release of endogenous
dopamine from striatal synaptosomes. The results of this study show that
CHEB possesses
hypnotic activity if its lethal
convulsant actions are blocked. The
hypnotic actions of
CHEB appear to correlate with inhibition of
voltage-dependent calcium channels in brain synaptosomes.