Is the hypothalamic paraventricular nucleus-locus coeruleus neuronal circuit involved in persistent increase in the plasma cortisol?

本研究旨在通过微透析和免疫组织化学技术，阐明在氨基甲酸乙酯和α-氯醛麻醉大鼠脑室内给予促肾上腺皮质激素释放因子诱导血浆皮质酮升高的中心机制。当促肾上腺皮质激素释放因子以0.5、1.5和3.0 nmol/动物脑室内剂量依赖性地增加下丘脑室旁核的去甲肾上腺素释放，但不增加肾上腺素释放。选择性促肾上腺皮质激素释放因子1受体拮抗剂CP-154,526（丁基乙基-{2,5-二甲基1-7-(2,4,6三甲基苯基1)- 7h -pyrrolo [2,3-d]嘧啶-4-基}胺）以1.3 mol/动物脑室剂量减弱促肾上腺皮质激素释放因子诱导的去甲肾上腺素释放，酚托拉明以0.66 mol/动物脑室剂量也消除促肾上腺皮质激素释放因子。非选择性烟碱胆碱受体拮抗剂六甲甲铵（1.8 μmol/动物）和强效α- 3β_2烟碱胆碱受体拮抗剂α-conotoxin MII （30 μmol/动物）、icicv （1.5 μmol/动物）可使下丘脑室旁核和血浆皮质酮的去甲肾上腺素释放量增加。在蓝斑区含有多巴胺-β-羟化酶的神经元和α_3烟碱受体亚单位表达的神经元上，icv诱导了cFos（即早期基因产物）的显著表达，而在含有去甲肾上腺素能神经元的髓质A_1和A_2区则不表达。提示中央给药促肾上腺皮质激素释放因子通过促肾上腺皮质激素释放因子1受体和含α_3亚单位的烟碱乙酰胆碱受体（可能是α_3 β_2烟碱乙酰胆碱受体）介导的蓝斑去甲肾上腺素能神经元向室旁核的激活，使血浆皮质酮升高

The present study was undertaken to clarify the central mechanisms, involved in the intracerebroventricularly administered corticotropin-releasing factor-induced elevation of plasma corticosterone in urethane- and α-chloralose-anesthetized rats using microdialysis and immunohistochemical techniques. When corticotropin-releasing factor was given at 0.5,1.5,and 3.0 nmol/animal intracerebroventricularly, it dose-dependently increased noradrenaline release but not adrenaline release in the hypothalamic paraventricular nucleus. The 1.5 nmol/animal dose of corticotropin-releasing factor-induced noradrenaline release was attenuated by CP-154,526 (butyl-ethyl-{2,5-dimethy1-7-(2,4,6trimethylpheny1)-7H-pyrrolo [2,3-d] pyrimidin-4-yl} amine), a selective corticotropin-releasing factor 1 receptor antagonist, at 1.3 mol/animal, intracerebroventricularly, and was also abolished by phentolamine at 0.66 mol/animal, intracerebroventricularly. In addition, the corticotropin-releasing factor-induced elev … More ation of noradrenaline release in-the hypothalamic paraventricular nucleus and plasma corticosterone were abolished by hexamethonium, a nonselective nicotinic acetylcholine receptor antagonist, at 1.8 μmol/animal, intracerebroventricularly, and α-conotoxin MII, a potent α_3β_2 nicotinic acetylcholine receptor antagonist, at 30 nmol/animal, i.c.v. Corticotropin-releasing factor at 1.5 nmol/animal, i.c.v. evoked a significant expression of cFos, an immediate-early gene product, on the dopamine-β-hydroxylase-containing neurons and α_3 nicotinic acetylcholine receptor subunit-expressing neurons in the locus coeruleus, but not in the medullary A_1 and A_2 regions containing noradrenergic neurons. These results suggest that centrally administered corticotrophin-releasing factor elevates plasma corticosterone by the corticotropin-releasing factor 1 receptor and α_3 subunit-containing nicotinic acetylcholine receptor (probably α_3 β_2 nicotinic acetylcholine receptor) mediated activation of the locus coeruleus noradrenergic neurons projecting to the paraventricular nucleus in rats Less