Locally applied progesterone metabolites alter neuronal responsiveness in the cerebellum

Ongoing studies in this laboratory have demonstrated that both systemically and locally administered sex steroids 17 beta estradiol (E2) and progesterone (P) alter cerebellar Purkinje cell responses to microiontophoretically applied amino acid neurotransmitters GABA and glutamate (GLUT) in the urethane-anesthetized, ovariectomized adult rat. In the present study, we have examined the effects of several locally pressure ejected P metabolites on Purkinje cell responsiveness to GABA and GLUT: 5 alpha-pregnane-20-one (5 alpha DHP), 5 alpha-pregnane-3 alpha-ol-20-one (3 alpha OH-DHP) and 5 alpha-pregnane-3 beta-ol-20-one (3 beta OH-DHP). GABA-induced inhibition was markedly enhanced immediately after onset of local application of 3 alpha OH-DHP or 5 alpha DHP, unaccompanied by alterations in background discharge. Both metabolites also attenuated excitatory responses to GLUT by 0-3 min after initiation of steroid application. In both cases, recovery to control levels of response was observed 6-9 min after termination of pressure application. These results are similar to those seen after local or systemic injection of P. In contrast, 3 beta OH-DHP did not produce any alteration in Purkinje cell responses to either amino acid. As 5 alpha DHP and 3 alpha OH-DHP can be localized in cerebellar tissue after P administration, the results presented here suggest that the neuronal effects of systemic P may be mediated by local membrane actions of P or its metabolites.