We tested the possibility that insulin-like growth factor I (IGF-I) acts as a neuromodulator in the adult cerebellar cortex since previous observations indicated that IGF-I is located in the olivo-cerebellar system encompassing the inferior olive and Purkinje cells. We found that conjoint administration of IGF-I and glutamate through a microdialysis probe stereotaxically implanted into the cerebellar cortex and deep cerebellar nuclei greatly depressed the release of gamma-aminobutyric acid (GABA), which normally follows a glutamate pulse. This inhibition was dose-dependent and long-lasting. Moreover, the effect was specific for glutamate since KCl-induced GABA release was not modified by IGF-I. Basic fibroblast growth factor, another growth-related peptide present in the cerebellum, did not alter the response of GABA to glutamate stimulation. In addition, electrical stimulation of the inferior olivary complex significantly raised IGF-I levels in the cerebellar cortex. Interestingly, when the inferior olive was stimulated in conjunction with glutamate administration, GABA release by cerebellar cells in response to subsequent glutamate pulses was depressed in a manner reminiscent of that seen after IGF-I. These findings indicate that IGF-I produces a long-lasting depression of GABA release by Purkinje cells in response to glutamate. IGF-I might be present in climbing fiber terminals and/or cells within the cerebellar cortex and thereby might affect Purkinje cell function. Whether this IGF-I-induced impairment of glutamate stimulation of Purkinje cells underlies functionally plastic processes such as long-term depression is open to question.