Correlation of sedative effects with brain levels of barbiturates in LS and SS mice.

Long-sleep (LS) and short-sleep (SS) mice, genetically selected for their differential CNS sensitivity to ethanol, have also been shown to differ in their response to other sedative-hypnotics, including the barbiturates. We have applied a gas-chromatographic method of analysis of brain barbiturate concentrations following IP administration of either the water-soluble barbiturate diethylbarbital (DB) or the lipid-soluble barbiturate secobarbital (SB). Brain barbiturate levels were assessed at loss of righting response, and at regaining righting response (waking). In addition, latency to loss of righting response and duration of loss of righting response were measured following IP barbiturate administration. We have observed a differential sensitivity of LS and SS mice to the sedative effects of DB, with LS mice having greater sensitivity compared to SS. This differential sensitivity to DB, as measured by a lower concentration of DB which caused loss of righting in LS, was accompanied by an equal rate of water-soluble barbiturate brain distribution and elimination in the two lines. With the lipid-soluble barbiturate SB, LS and SS mice did not differ in brain SB concentration at loss of righting response or at waking. However, sleep time was much longer in SS mice than LS due to slower brain clearance of the barbiturate in SS. Therefore, duration of loss of righting (sleep time) did not adequately reflect central sensitivity to the lipid-soluble barbiturate. These data suggest the importance of quantifying brain concentrations at loss of righting reflex when assessing central sensitivity to sedative-hypnotic agents.(ABSTRACT TRUNCATED AT 250 WORDS)