Marked variation in diazepam sensitivity in Swiss albino mice.

Using the righting reflex as the critical level, sleep was measured in Swiss albino mice at a dose of 35 mg/kg diazepam, i.p. Sleep times varied markedly from zero to 120 min with a mean +/- s.d. of 44 +/- 37 (N = 202). The distribution is skewed to the left with a coefficient of skewness of 0.33 +/- 0.17. The sleep times of the two sexes, when analyzed separately, showed similar range, mean and s.d., except that the distribution tended to be more clearly bimodal in males than in females. These animals also exhibited marked variations in their response to either ethanol (4 g/kg) or pentobarbital (45 mg/kg). The diazepam sleep time failed to correlate with the ethanol sleep time. Significant correlation, however, was obtained between diazepam and pentobarbital sleep times. On further analysis with least-squares fit to a straight line, the data yielded a line with a slope of 0.16; thus despite the correlation reaching a significant level, there is no significant difference in the pentobarbital sleep times between mice that have the longest or the shortest diazepam sleep times. By monitoring the plasma and brain levels of diazepam and N-desmethyldiazepam in mice at awakening, it was found that the variations in sleep time cannot be explained by individual differences in drug disposition. The phenomenon is discussed in terms of individual variations in diazepam sensitivity and the possibility of development of tolerance to diazepam almost immediately after diazepam administration.

Acute tolerance to diazepam in mice: pharmacokinetic considerations.

The tolerance to the hypnotic effect of diazepam developed after a single exposure to diazepam in the presence or absence of cycloheximide, which blocks liver enzyme induction, was studied. At the high dose (30-35 mg/kg) used in this study, diazepam was found to be metabolized very rapidly in mice, consistent with previous findings using a much smaller dose (5 mg/kg). There was no significant difference in the pharmacokinetics of diazepam in control and tolerant mice as observed by monitoring the plasma and brain concentrations of diazepam and N-desmethyldiazepam. It is concluded that acute tolerance to diazepam in mice may not be attributed to changes in pharmacokinetic factors.

Acute tolerance to diazepam induced by benzodiazepines.

It was observed that the effectiveness of diazepam in causing sleep, as defined by the loss of righting reflex, was significantly decreased after a single exposure to either diazepam or lorazepam. RO 15-1788, a benzodiazepine antagonist, in contrast did not induce tolerance to diazepam. The mechanism for this acute tolerance is unclear. The rapidity in its development may exclude metabolic tolerance while alterations in brain sensitivity to diazepam remain a possibility.

Adrenoreceptor-mediated responses in the isolated portal vein of the hypothyroid rat.

1 The effect of hypothyroidism, induced by methimazole, upon the response of the isolated portal vein of the rat to adrenoceptor agonists and antagonists, to angiotensin II and to papaverine has been investigated. 2 The positions and maxima of log doses-response curves, to the vasoconstrictor agonists, noradrenaline and angiotensin II, and to the vasodilator agonists isoprenaline and papaverine, were unaffected by methimazole treatment. 3 The alpha-adrenoreceptor antagonist phentolamine competitively inhibited the effects of noradrenaline to a similar extent in preparations from control and hypothyroid animals. The competitive antagonism of isoprenaline by the beta-adrenoreceptor antagonist propranolol was similarly unaffected by hypothyroidism. 4 These results taken together indicate that hypothyroidism is without significant effect upon either the properties of postjunctional alpha- and beta-adrenoreceptors in the rat portal vein, or upon the reactivity of this blood vessel to the vasoactive agonists studied.