INVOLVEMENT OF PROTEIN-KINASE-C AND NITRIC-OXIDE IN THE MODULATION BYINSULIN-LIKE GROWTH-FACTOR-I OF GLUTAMATE-INDUCED GABA RELEASE IN THECEREBELLUM

Insulin-like growth factor-I elicits a long-term depression of the glu tamate-induced GABA release in the adult rat cerebellum that lasts at least several hours, We studied whether protein kinase C and nitric ox ide may be involved in this effect of insulin-like growth factor-I on GABA release since both signalling pathways have been implicated in ot her forms of neuromodulation in the cerebellum, By using microdialysis in the adult rat cerebellum, we found that either an inhibitor of pro tein kinase C (staurosporine) or of nitric oxide synthase (Nw-nitro-L- arginine methyl ester) counteracted the long-term, but not the acute e ffects of insulin-like growth factor-I on glutamate-induced GABA relea se, On the contrary, when either an activator of protein kinase C (pho rbol ester), or an nitric oxide donor (L-arginine), were given with gl utamate, they mimicked only the acute effects of insulin-like growth f actor-I on glutamate-induced GABA release, Finally, when both protein kinase C and nitric oxide-synthase were simultaneously inhibited by co njoint administration of staurosporine and Nw-nitro-L-arginine methyl ester, a complete blockage of both the short and the long-term effects of insulin-like growth factor-I on GABA release was obtained, These r esults, indicate that: (i) activation by insulin-like growth factor-I of either the protein kinase C or nitric oxide-signalling pathways is sufficient for the short-term inhibition of glutamate-induced GABA rel ease; and (ii) simultaneous activation of both the protein kinase C an d the nitric oxide signalling pathways is necessary for insulin-like g rowth factor-I to induce a long-term depression of GABA responses to g lutamate. Thus, long-term depression of glutamate-induced GABA release by insulin-like growth factor-I in the cerebellum is mediated by simu ltaneous activation of both protein kinase C and nitric oxide-signalli ng pathways.