Determination of Halothane‐induced Sleeping Time in the Rat: Effect of Prior Administration of Centrally Active Drugs

Abstract

I A method is described for the determination of halothane-induced sleeping time in the rat. 2 The sleeping time exhibited a diurnal variation which was due, at least in part, to a change in the sensitivity of the central nervous system (CNS) to the anaesthetic. 3 Tolerance to halothane did not develop in rats repeatedly exposed to the anaesthetic over a period of over 48 hours. 4 Repeated sleeping time determinations have been used to follow changes in the sensitivity of the CNS to the anaesthetic occurring with time. 5 A tolerance to halothane was induced by pretreatment of rats with doses of amylobarbitone, pentobarbitone or meprobamate sufficient to keep animals anaesthetized for approximately 12 hours. This tolerance was followed by a period of halothane-hypersensitivity. 6 Halothane-tolerant animals awakened with higher brain halothane concentrations and were also tolerant to intracerebroventricularly administered pentobarbitone. 7 Halothane-hypersensitive rats awakened with lower brain halothane concentrations and were also hypersentive to intracerebroventricularly administered pentobarbitone. 8 The possibility that the induction of cross-tolerance to halothane may, be indicative of a drug's potential to produce dependence is discussed.

HYPOTENSIVE AND SEDATIVE EFFECTS OF α‐ADRENOCEPTOR AGONISTS: RELATIONSHIP TO α1‐AND α2‐ADRENOCEPTOR POTENCY

“…Potentiation of halothane-induced anaesthesia Turnbull & Watkins (1976) have shown that potentiation of halothane-induced anaesthesia is a reliable way to assess the sedative action of drugs and has several advantages over other methods of assessing sedation. The most important of these are the rapid and smooth onset of the anaesthesia and the prompt recovery following its withdrawal.…”

PROCEEDINGS OF THE British Pharmacological Society 10th‐12th September, 1980

“…We have demonstrated that acute administration of high doses, or chronic administration of low doses, of CNS depressant drugs leads to a withdrawal hyperexcitability of the CNS in the rat (Turnbull & Watkins, 1976a;Turnbull & Watkins, 1976b). We have measured the change in excitability of the CNS by determining the sensitivity of the animals to the anaesthetic halothane.…”

“…Recent debate on the liability of benzodiazepines to induce physical dependence has prompted us to examine some of these drugs in our halothaneinduced sleeping time model. We have previously demonstrated that when hypnotics such as barbiturates or meprobamate are withdrawn following administration of very large doses acutely (Turnbull & Watkins, 1976a) or small doses chronically (Turnbull & Watkins, 1976b) a CNS hyperexcitability is produced and this can be quantitated by measuring the decreased sensitivity of animals to halothane. This decrease was often followed by a rebound increase in sensitivity to halothane before return to normal.…”

“…Tween 80. Halothane sleeping time, measured according to the method of Turnbull & Watkins (1976a) was determined at 4 h intervals beginning 6 h after the last injection and the results expressed as % ± s.e. mean of control.…”

“…We have thus demonstrated that acute administration of high doses or chronic administration of low doses of benzodiazepines leads to a withdrawal hyperexcitability of the CNS as indicated by the change in sensitivity to halothane. & WATKINS, J.W. (1976a).…”