EFFECTS OF CHRONIC ADMINISTRATION AND SUBSEQUENT WITHDRAWAL OF ETHANOL-CONTAINING LIQUID DIET ON RAT-LIVER TRYPTOPHAN-PYRROLASE AND TRYPTOPHAN-METABOLISM

An investigation of the effects of chronic administration of ethanol b y the liquid diet procedure and its subsequent withdrawal on tryptopha n (Trp) metabolism and disposition was performed in rats. Treatment wi th the control liquid diet caused an enhancement of liver Trp pyrrolas e activity and mRNA abundance. These effects are not due to the starva tion associated with this feeding procedure. because they occur in rat s maintained on the liquid diet ad libitum. Chronic ethanol administra tion in the liquid diet did not further influence the above increased expression of Trp pyrrolase mRNA but caused inhibition of pyrrolase ac tivity in competition with the effects of the diet. The control liquid diet decreased liver Trp concentration. but exerted no significant ef fects on other aspects of Trp disposition. The most striking and robus t finding was a highly significant elevation in both Trp pyrrolase act ivity and mRNA expression at 7h following discontinuation of ethanol a vailability. at which time there were demonstrable behavioural signs o f ethanol withdrawal. The increase in Trp pyrrolase mRNA during alcoho l withdrawal may be caused by corticosterone. whose circulating concen tration was also increased. The changes in Trp pyrrolase activity duri ng ethanol withdrawal were associated with significant alterations in Trp disposition including decreased brain Trp concentration and 5-hydr oxytryptamine synthesis and turnover. These alterations may play a piv otal role in the behavioural manifestations of ethanol withdrawal incl uding the hyperexcitement underlying audiogenic seizures. We suggest t hat rat Trp pyrrolase gene regulation may be an important biological d eterminant of the ethanol withdrawal syndrome and requires further stu dy. and that the use of the liquid diet procedure in Trp metabolic stu dies requites inclusion of adequate controls and special attention to the effects of the liquid diet itself.