Suppression of the induction of long-term depression by carbon monoxide inrat cerebellar slices

Carbon monoxide (CO) suppresses brain functions at doses lower than that su ppressing oxygen (O-2) supply to the brain, and the cerebellum is one of th e sites most susceptible to the neurotoxic effects of CO. We investigated t he effects of CO on the induction of cerebellar long-term depression (LTD) in the synapses between parallel fibres (PFs) and Purkinje cells. CO, at co ncentrations between 8 nM and 5 muM, exhibited almost no effect on synaptic responses in Purkinje cells, O-2 consumption and NO release from PFs in ra t cerebellar slices. However, the induction of LTD was significantly suppre ssed by CO at concentrations between 40 and 200 nM. The suppressive effect of 40 nM CO was antagonized by 10 muM NOR3, an NO donor. In contrast, CO ex hibited no clear effect on the induction of LTD at concentrations between 1 and 5 muM. The induction of LTD, suppressed by 10 muM N-G-nitro-L-arginine , an inhibitor of NO synthase, was not restored by 5 muM CO. CO is not only a neurotoxic substance but also a candidate for an intercellular messenger . delta -Aminolevulinate (30 muM), a substance facilitating endogenous CO p roduction, suppressed the induction of LTD, and the effect of delta -aminol evulinate was antagonized by 10 muM NOR3. These findings suggest that CO ma y have a suppressive effect on the induction of cerebellar LTD at nanomolar concentrations, probably via its effects on NO/cGMP signalling.