Biphasic effect of doxapram on hypnotic activity of pentobarbital in mice

The effect of doxapram, a respiratory stimulant, on the pentobarbital sleeping time was investigated in mice. The sleeping time induced by the intraperitoneal injection of pentobarbital was prolonged 0--120 min after the administration of doxapram (25-100 mg/kg, i.p.). The pretreatment with doxapram 60 min before had no effect on the anesthetic time induced by ether and on the sleeping time induced by the intracerebroventricular injection of pentobarbital, while increased the lethality of pentobarbital only slightly and the levels of pentobarbital in the plasma and brain significantly. The activities of pentobarbital oxidase and aminopyrine N-demethylase in the 9000 X g supernatant fraction of the liver were inhibited by the pretreatment with doxapram 60 min before the test. On the other hand, 12-24 hr after the injection of doxapram the pentobarbital sleeping time was markedly shortened. Thus, the biphasic effect of doxapram, prolongation at first and shortening later, on the pentobarbital sleeping time was observed. It is possible that doxapram inhibits the hepatic microsomal drug-metabolizing enzymes without an increase in the sensitivity of the central nervous system at first and stimulates these enzymes during the second phase.