Mechanisms contributing to barbiturate intolerance in rats.

1. Female rats, 3 weeks after pretreatment with 200 or 400 (mg/kg)/day barbitone for 2 or 30 days, exhibited a prolonged sleeping time and a reduced awakening barbiturate brain level when challenged with either barbitone or pentobarbitone. After 3 additional weeks, the latter responses had returned, or were returning to, control values.2. Barbitone pretreatment schedules had no residual effect upon in vitro hepatic pentobarbitone-metabolizing activity measured 3 or 6 weeks later, except in one instance, when hepatic enzyme activity was significantly enhanced 3 weeks after 30 daily doses of 200 mg/kg barbitone. In this case, however, an enhanced barbiturate sleeping time, together with a reduced awakening barbiturate brain level, were observed.3. It is concluded that barbitone administered intraperitoneally in doses of 200 to 400 (mg/kg)/day for 2 or 30 days induces a non-hepatogenic intolerance to barbiturates, related to an increased sensitivity of the central nervous system to these drugs. This central intolerance is seen 3 weeks, but not 6 weeks, after pretreatment. Furthermore, this central intolerance has been observed to co-exist with an hepatic tolerance, a situation which could result in a reduced LD(50) coupled with an increase in ED(50).