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 17β 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: 5α-pregnane-20-one (5α DHP), 5α-pregnane-3α-ol-20-one (3α OH-DHP) and 5α-pregnane-3β-ol-20-one (3β OH-DHP). GABA-induced inhibition was markedly enhanced immediately after onset of local application of 3α OH-DHP or 5α 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, 3β OH-DHP did not produce any alteration in Purkinje cell responses to either amino acid. As 5α DHP and 3α 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.