Prolonged hypothermia after phenobarbital-induced anesthesia in adrenalectomized rats.

Adrenalectomized rats are hypersensitive to the hypothermic as well as hypnotic effects of phenobarbital. The exaggerated hypnotic response is more pronounced in the chronic (10 day) than the acute (1 day) adrenalectomized rat and is reversed by glucocorticoid replacement. The prolonged hypothermia to a hypnotic dose of phenobarbital occurs in adrenalectomized but not adrenodemedullated rats. This hypersensitivity is characterized by an impaired ability to regain normal body temperatures for as long as 24 hours after regaining the righting reflex. The prolonged hypothermia is prevented by prior treatment with glucocorticoids but not mineralocorticoids. There appears to be no gross alteration in disposition of phenobarbital following adrenalectomy suggesting that the prolonged duration of hypothermia is not a consequence of accumulation of the drug.

The role of cerebral serotonin in the development of tolerance to centrally administered phenobarbital.

Chronic intracerebroventricular injection of phenobarbital results in the development of tolerance to the depressant effects of the drug. The neurotransmitters involved and the manner in which cerebral neurons adapt to this depressant effect are at present unknown. This study examines whether brain serotonin containing neurons participate in the attenuation of the hypnotic response caused by chronic barbiturate administration. Depletion of serotonin with p-chlorophenylalanine, p-chloroamphetamine and 5,7-dihydroxytryptamine did not affect the initial dose-response curve to the centrally injected barbiturate, but all treatments resulted in significant delays in tolerance development. A negative correlation between the extent of whole brain serotonin remaining and the duration of loss of righting reflex on the last day of the chronic phenobarbital regimen was obtained after pretreatment with p-chlorophenylalanine, p-chloroamphetamine and saline. The sleep times of animals pretreated with 5,7-dihydroxytryptamine did not fit this linear relationship. Treatment with p-chloroamphetamine after cessation of the chronic phenobarbital regimen did not influence the rate of tolerance reversal. Steady state levels of serotonin and the concentration of its metabolite, 5-hydroxyindoleacetic acid, in different brain areas were comparable in controls and tolerant rats when examined at various stages intolerance development. However, tolerant and non-tolerant rats sacrificed at time points immmediately after central phenobarbital injection had different temporal patterns of 5-hydroxyindoleacetic acid elevation in the striatum, hypothalamus and midbrain which were observable only during the loss of righting reflex. The data indicate that cerebral serotonin neurons participate in the attenuation of hypnosis following chronic phenobarbital injections.

Cross-tolerance to centrally injected barbiturates.

Hypnotic responses to intracerebroventricular (i.c.v) injections of either barbital, pentobarbital, R(-) and S(+) mephorbarbital, or racemic metharbital were compared to those produced by phenobarbital. Dose--response relationships were obtained for all except S(+) mephorbarbital and metharbital. Chronic i.c.v. phenobarbital administration resulted in tolerance to the drug's hypnotic effects. However, chronic barbital administration using an identical regimen did not produce tolerance, nor were phenobarbital tolerant rats cross-tolerant to barbital. Chronic i.c.v pentobarbital resulted in an irreversible decrease in responsiveness to its own effects and to those of other barbiturates. This was attributed to the high alkalinity of the solution (pH 9.6) since i.c.v. injection of saline adjusted to the same pH also reduced responsiveness to i.c.v. barbiturates. However, rats tolerant to i.c.v. phenobarbital were tolerant to acute i.c.v. injection of pentobarbital. Similar cross-tolerance was observed on systemic administration of the barbiturates. The efflux rates of i.c.v. phenobarbital or barbital and their distribution to different brain areas were identical in tolerant and nontolerant rats. Awakening phenobarbital brain levels of the tolerant rats were approximately three times higher than those in nontolerant controls. The conclusion is reached that central administration of phenobarbital provides a valid model for studying functional tolerance.

Prevention and reversal of tolerance to barbiturates by intraventricular injection of hemicholinium-3.

Intracerebroventricular (i.c.v.) injection of phenobarbital, 800 mug, or intraperitoneal (i.p.) injection of hexobarbital, 100 mg/kg, into rats resulted in a loss of righting reflex lasting 15.4 +/- 0.2 min and 20.7 +/- 0.7 min, respectively. A 40-60% reduction in this response was obtained following administration of phenobarbital either i.c.v. (800 mug 4 times daily) or i.p. (80 mg/kg/day) for 4 days. Although these treatments also increased hepatic mixed function oxidase activity, this enzyme induction was shown to be unrelated to the development of tolerance to loss of righting reflex. I.c.v. injection of hemicholinium-3 (HC-3) in doses which reduce brain acetylcholine levels (4-20 mug) profoundly affected tolerance to the central depressant effect of the barbiturates. Thus, depending upon the time of administration, HC-3 either retarded or prevented development of this tolerance. Moreover, if tolerance was allowed to progress normally, administration of HC-3 on day 4 or 5 returned the duration of the loss of righting reflex toward normal values. HC-3 did not influence either the duration of this response in non-tolerant rats or the induction of the hepatic mixed function oxidase activity. These results suggest that brain ACh plays an important role in the development and maintenance of tolerance to the central depressant effects of barbiturates.