Inactivation by acivicin of rat brain CTP and GMP synthetases and depression of CTP and GTP concentrations.

Evidence was provided that injection of acivicin (25 mg/kg, i.p.) into the rat inactivated brain CTP and GMP synthetases. Under the same circumstances, CTP and GTP concentrations in the rat brain decreased following the decline in the activities of CTP and GMP synthetases. The decrease in enzymic activities and nucleotide concentrations progressed with time. The decline in CTP and GMP synthetase activities and CTP and GTP concentrations caused by acivicin occurred more slowly and to a lesser extent than in liver and hepatoma 3924A. The delay in the expression of acivicin action in the rat brain was attributed to a possible slower entrance of acivicin and the lower concentration than might have been attained in the rat brain. These considerations are based on the rapid disappearance of acivicin from rat plasma noted earlier. The decline in CTP concentration in rat brain might interfere with neuronal function. The decline in GTP concentration might be expressed through the depletion of biopterins which are generated from GTP in the brain. The possible relevance to the biochemical basis of paranoid schizophrenia which occurs reversibly after high-dose acivicin or tiazofurin treatment was discussed.