Cyclic nucleotide concentrations in the brains of mice treated with the convulsant bicyclic organophosphate, 4-isopropyl-2,6,7-trioxa-1 -phosphabicyclo[2,2,2] octane

Abstract

The possible involvement of brain cyclic nucleotides in the mechanism of toxicity of 4-alkyl-2,6,7-trioxa-l-phosphabicyclo[2,2,2]octanes—convulsant bicyclic organophosphates without anticholinesterase properties—has been studied by examining the effects of the intracerebroventricular application of the 4-isopropyl derivative (IPTBO) on the concentrations of cyclic AMP and cyclic GMP in three subsections of the brain of the mouse. IPTBO and caffeine, a convulsant phosphodiesterase inhibitor included in the study for comparison, produced convulsions accompanied by decreases in the cyclic AMP concentrations in the cortex, the subcortex and the cerebellum, and increases in the cyclic GMP concentrations in the subcortex and the cerebellum. Pretreatment with penlobarbitonc (intraperitoneally) protected against convulsions and the concomitant changes in the cyclic nucleotides produced by IPTBO. In contrast. Soman, a potent convulsant anticholinesterase, produced a convulsive state with increased levels of cyclic GMP and cyclic AMP in the cerebellum and the cortex. A speculative scheme is proposed (i) to explain the results, which do not appear to support the direct involvement of the inhibition of the brain cyclic nucleotide phosphodiesterase in the mechanism of toxicity of the bicyclie organophosphates or caffeine, and (ii) to provide some basis for further study.