Acute Stimulatory Effect of Estradiol on Striatal Dopamine Synthesis

Abstract: The acute effect of physiological doses of estradiol (E2) on the dopaminergic activity in the striatum was studied. In a first series of experiments, ovariectomized rats were injected with 17α or 17β E2 (125, 250, or 500 ng/kg of body weight, s.c.), and in situ tyrosine hydroxylase (TH) activity (determined by DOPA accumulation in the striatum after intraperitoneal administration of NSD 1015) was quantified. A dose‐dependent increase in striatal TH activity was observed within minutes after 17β (but not 17α) E2 treatment. To examine whether E2 acts directly on the striatum, in a second series of experiments, anesthetized rats were implanted in the striatum with a push‐pull cannula supplied with an artificial CSF containing 3 Htyrosine. The extracellular concentrations of total and tritiated dopamine (DA) and 3,4‐dihydroxyphenylacetic acid (DOPAC) were measured at 20‐min intervals. Addition of 10 −9 M 17β (but not 17α) E2 to the superfusing fluid immediately evoked an ∼50% increase in 3 HDA and 3 HDOPAC extracellular concentrations, but total DA and DOPAC concentrations remained constant. This selective increase in the newly synthesized DA and DOPAC release suggested that E2 affects DA synthesis rather than DA release. Finally, to determine whether this rapid E2‐induced stimulation of DA synthesis was a consequence of an increase in TH level of phosphorylation, the enzyme constant of inhibition by DA ( K i DA ) was calculated. Incubation of striatal slices in the presence of 10 −9 M 17β (but not 17α) E2 indeed evoked an approximate twofold increase in the K i DA of one form of the enzyme. It is concluded that physiological levels of E2 can act directly on striatal tissue to stimulate DA synthesis. This stimulation appears to be mediated, at least in part, by a decrease in TH susceptibility to end‐product inhibition, presumably due to phosphorylation of the enzyme. The rapid onset of this effect, and the fact that the striatum does not contain detectable nuclear E2 receptors, suggest a nongenomic action of the steroid.