Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters.

In a preliminary report we have shown that both intravenous and local application of progesterone (P) are capable of increasing cerebellar Purkinje cell responsiveness to microiontophoretically applied gamma-aminobutyric acid (GABA) and decreasing responsiveness to glutamate (GLUT) in the urethane-anesthetized, ovariectomized adult rat. In the present study we have examined the time course of effects of several doses of P and different combinations of both E2 and P on responses of individual Purkinje cells to GABA and GLUT. Extracellular activity of single Purkinje neurons was recorded using multibarrel glass micropipets. Spontaneous firing rate and responses of neurons to microiontophoretic pulses (10 s pulses every 40 s) of GABA (10-50 nA) and GLUT (3-40 nA) were examined before and after jugular i.v. administration of P or E2/P combinations to ovariectomized rats. In some cases animals received s.c. injections of E2 (2 micrograms) at 24 and 48 h before the day of recording. This injection schedule results in maximal reproductive effects of P. Within 5-15 min after P administration (5,50 or 500 micrograms) to ovariectomized rats, Purkinje cell responses to GLUT were decreased by 87%, and inhibitory responses to GABA were increased by 50%, with no associated change in spontaneous firing rate. In addition, the magnitude of the change in amino acid response was directly proportional to the dose of P. In most cases, complete recovery was observed 20-45 min after P administration. E2 pretreatment did not alter these P-induced effects. Combinations of E2 (300 ng/kg) and P (50 or 500 micrograms) injected simultaneously resulted in effects on GLUT responsiveness which were similar to those seen with P alone, while effects similar to E2 alone were observed with administration of E2 plus P at 5 micrograms. The administration of a protein synthesis inhibitor, anisomycin (30 mg/kg, i.v.), 20 min before the recording session did not prevent any of the above steroid effects. These results indicate that sex steroids can act to alter neuronal responsiveness to putative neurotransmitters in a CNS region not known to contain steroid receptors and that the particular combination of steroids will determine the neuronal response. These findings further suggest that the observed steroid-induced alterations in Purkinje cell responsiveness do not appear to require genomic mechanisms.