エストロゲンの中枢ニューロン作用—即時反応のメカニズムについて

Mechanism underlying the rapid effect of estradiol on medial amygdala and ventromedial hypothalamic neurons.

I．はじめに

　エストロゲンの中枢作用としては情動反応^3），摂食行動^4,21），神経回路網の維持と再生^13）など実に多様である。一方，エストロゲンの中枢作用のニューロンレベルでの作用は従来，細胞質内のエストロゲンレセプターと結合し核内のRNA依存性蛋白合成系を制御することによるという報告工^4）と，エストロゲンが短潜時でニューロンの電気活動を変化させるいわゆる速効性効果^6,22）とが報告されていたが，実際にニューロンの膜電位がどのように変化するかについては報告がなく，不明な点も多い。

　扁桃体内側核は摂食行動^4），ゴナドトロピン分泌^5），排卵^5）などに，視床下部腹内側核は摂食行動^21），ロードーシス^16）などに関係したエストロゲンの作用部位であるが，最近われわれは，これらの部位においてエストロゲンが蛋白合成系を介さず膜に直接作用し，ニューロンの興奮性を変化させることを明らかにした^9,12）。

The effects of estradiol on neural excitability of the medial amygdala (Med-AMG) and the ventro-medial hypothalamus (VMH) were studied. Intracellular recordings were made from Med-AMG and VMH neurons to define the mechanism of the rapid effect on the neural membrane in vitro. All female rats and guinea pigs were ovariectomized bilaterally and two weeks after the operation, a single priming of estradiol benzoate was injected subcutaneously. Two days later, coronal brain slices were obtained. 17 β-estradiol hyperpolarized 19 of 70 Med-AMG neurons accompanied by a decreased membrane input resistance. The reversal potential for the hyperpolarization shifted by change in external K⁺ concentra-tions. The estradiol hyperpolarization persisted under the elimination of synaptic inputs by use of Ca2+ free solution or the suppression of protein synthesis by actinomycin D or cycloheximide. The degree of the estradiol hyperpolarization was changed according to the 17 β-estradiol concentration. These results indicate that 17 β-estradiol directly, without mediation of protein synthesis, increased K⁺ conductance of the postsynaptic membranes. Significant difference of the estradiol-responding rates between male (8%) and female (27%) were demonstrated. In VMH neurons, 14 of 73 neurons, 12 of those had IA conductance, were depolarized by 17β-estradiol with a decreased: membrane K⁺ conductance. This depolarization was attenuated by application cf imidazole, whereas augmented by application of iso-butylmethylxanthin (IBMX) or forskolin. From this evidence, 17β-estradiol depolarization could be mediated through an increase in intracellular cyclic AMP. On the other hand, 24 of 73 neurons, 19 of these showed low-threshold response, were hyperpolarized in association with an increased membrane K⁺ conductance. This hyperpolarization was attenuated by application of imidazole and augmented by IBMX, samely as the depolarization. However, forskolin did not affect the estradiol hyperpolarization. This indicates that the estradiol hyperpolarization may be mediated by some cyclic nucleotide other than cyclic AMP. Med-AMG and VMH neurons showed the rapid responses, i.e. hyperpolarization and de-polarization, to estrogen. These responses might be due to change in K⁺ permeability through media-tion of cyclic nucleotides. These estradiol-evoked ffects on neuronal excitability of these nucleus could be involved in integration of chemosenscry information for such as food intake.