Givalois L, Grinevich V, Li S, Garcia-De-Yebenes E, Pelletier G
Cerebral Plasticity Laboratory, EP 628-CNRS, Montpellier II University, France.
Neuroscience. 1998 Jul;85(2):557-67. doi: 10.1016/s0306-4522(97)00650-7.
The involvement of endogenous benzodiazepine octadecaneuropeptide in the regulation of corticotropin-releasing hormone messenger RNA expression has been studied using in situ hybridization technique. Intracerebroventricular injection of octadecaneuropeptide (4 microg/kg) induced a 26% decrease in the corticotropin-releasing hormone messenger RNA expression in the hypothalamic paraventricular nucleus. Concomitant injection of octadecaneuropeptide and i.p. injection of the GABA(A) receptor agonist muscimol (4 mg/kg) potentiated the corticotropin-releasing hormone messenger RNA decrease ( - 34%). The depressing effect of octadecaneuropeptide on corticotropin-releasing hormone gene expression was totally reversed by pretreatment of the animals with the GABA(A) receptor antagonist picrotoxin (5 mg/kg; i.p.) or by pretreatment with the benzodiazepine receptor antagonist flumazenil (4 mg/kg; i.p.). To determine the reciprocal involvement of adrenal and sexual steroids in this regulation, animals are adrenalectomized and/or castrated. Adrenalectomy reversed the effect induced by octadecaneuropeptide, which increased corticotropin-releasing hormone messenger RNA expression (+21%), while castration did not modify the negative influence of octadecaneuropeptide. When rats were adrenalectomized and castrated, the adrenalectomy influence was predominant, since octadecaneuropeptide increased significantly the hybridization signal (+18%). The involvement of neurosteroids, especially reduced metabolites of progesterone was also investigated. The concomitant injection of octadecaneuropeptide and subcutaneous injection of the 5alpha-reductase inhibitor MK-906 (14 mg/kg) to adrenalectomized and castrated rats, reduced significantly by 60% the increase of corticotropin-releasing hormone messenger RNA expression induced by octadecaneuropeptide. These results indicate that in vivo the endogenous benzodiazepine octadecaneuropeptide, via an activation of the benzodiazepine sites of the GABA(A) receptor, negatively modulates corticotropin-releasing hormone neuronal activity and that this modulation can be negatively or positively influenced by central and peripheral steroids.
利用原位杂交技术研究了内源性苯二氮卓十八烷肽在促肾上腺皮质激素释放激素信使核糖核酸表达调节中的作用。脑室内注射十八烷肽（4微克/千克）可使下丘脑室旁核中促肾上腺皮质激素释放激素信使核糖核酸的表达降低26%。同时注射十八烷肽和腹腔注射GABA(A)受体激动剂蝇蕈醇（4毫克/千克）可增强促肾上腺皮质激素释放激素信使核糖核酸的降低幅度（-34%）。十八烷肽对促肾上腺皮质激素释放激素基因表达的抑制作用可通过用GABA(A)受体拮抗剂印防己毒素（5毫克/千克；腹腔注射）预处理动物或用苯二氮卓受体拮抗剂氟马西尼（4毫克/千克；腹腔注射）预处理而完全逆转。为了确定肾上腺和性类固醇在这种调节中的相互作用，对动物进行肾上腺切除术和/或去势。肾上腺切除术逆转了十八烷肽诱导的作用，十八烷肽使促肾上腺皮质激素释放激素信使核糖核酸表达增加（+21%），而去势并未改变十八烷肽的负面影响。当大鼠进行肾上腺切除术和去势时，肾上腺切除术的影响占主导，因为十八烷肽显著增加了杂交信号（+18%）。还研究了神经甾体的作用，尤其是孕酮的还原代谢产物。对肾上腺切除和去势的大鼠同时注射十八烷肽和皮下注射5α-还原酶抑制剂MK-906（14毫克/千克），可使十八烷肽诱导的促肾上腺皮质激素释放激素信使核糖核酸表达增加显著降低60%。这些结果表明，在体内，内源性苯二氮卓十八烷肽通过激活GABA(A)受体的苯二氮卓位点，对促肾上腺皮质激素释放激素神经元活性产生负调节作用，并且这种调节可受到中枢和外周类固醇的负性或正性影响。
