Inhibition of Acute CNS‐Tolerance to Hexobarbital and Prolongation of Hexobarbital Anaesthesia by Disulfiram Treatment in Rats

In many studies disulfiram treatment has been found to prolong hexobarbital anaesthesia, but the underlying mechanisms have not been clarified. In the present study, the effect of disulfiram on the development of acute tolerance to hexobarbital was studied in 2 age groups of rats (80 and 130 days old). Acute tolerance was measured as the increase in the brain concentration of hexobarbital (in 4 brain regions) needed to keep the rats on a constant EEG-monitored anaesthetic level for 1 hr. The effects of disulfiram on the metabolism in vitro and elimination in vivo of hexobarbital were also measured. The results suggest that the prolonged hexobarbital anaesthesia found after disulfiram treatment was the result of an inhibition of at least two different mechanisms: (1) the ability of the brain to develop acute tolerance to hexobarbital, and (2) the metabolism of hexobarbital by the liver, the latter resulting in a decreased elimination of the anaesthetic from the brain. The impaired development of acute tolerance was apparent only in the older rats. The inhibition of hexobarbital metabolism was most obvious in the younger ones.