Johnson M P, Kelly G, Chamberlain M
Neuroscience Research, Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
J Neuroendocrinol. 2001 Aug;13(8):670-7. doi: 10.1046/j.1365-2826.2001.00678.x.
From previous work, it appears that glutamate can activate the hypothalamic-pituitary-adrenocortical (HPA) axis by an interaction at either ionotopic or metabotropic (G-protein coupled) receptors. For example, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD), a metabotropic glutamate (mGlu) receptor agonist, has been shown to increase the levels of serum corticosterone in rats. The present study was undertaken to further characterize which of the mGlu receptors are substantially involved in control of the HPA axis. The group I mGlu receptor agonists, 3,5-dihydroxyphenylglycine (DHPG), 1S,3R-ACPD, and 2-chloro-5-hydroxyphenylglycine (CHPG) but not the inactive isomer 1R,3S-ACPD were found to dose-dependently increase serum corticosterone 1 h after intracerebroventricular (i.c.v.) injection in male rats. The relative potency, DHPG (EC50 = 520 nmol) > 1S,3R-ACPD (1.4 micromol) = CHPG (2.7 micromol) >> 1R,3S-ACPD (>> 3 micromol) is consistent with activation of group I (mGlu1/5) receptors. The effects of DHPG were long lasting with substantial elevations in corticosterone remaining for at least 3 h. In a similar manner, the group III mGlu receptor agonists, L-AP4 (4-phosphono-2-aminobutyric acid) and L-SOP (serine-O-phosphate), were found to increase serum corticosterone levels at 1 h. In contrast, the mGlu group II selective agonists LY354740 (10 mg/kg, i.p.) and subtype-selective doses of the group II antagonist LY341495 (1 mg/kg, i.p.) did not significantly elevate serum corticosterone. Given the group I agonists results, it was surprising to find that group I selective and mGlu1 selective antagonists given alone also increased serum corticosterone. As with the agonists, the rise in serum corticosterone with LY393675 (an mGlu1/5 antagonist, EC50 = 20 nmol, i.c.v.) and LY367385 (an mGlu1 antagonist, 325 nmol, i.c.v.) were dose-dependent and consistent with their relative affinity for the group I mGlu receptors. The selective mGlu5 antagonist MPEP [2-methyl-6-(phenylethylnyl)pyridine] increased serum corticosterone but only at high doses (> 30 mg/kg, i.p.). A model involving the high glutamatergic tone on GABAergic interneurons in the paraventricular nucleus of the hypothalamus is discussed as a possible explanation for these results.
从先前的研究工作来看，谷氨酸似乎可以通过与离子型或代谢型（G蛋白偶联）受体相互作用来激活下丘脑 - 垂体 - 肾上腺皮质（HPA）轴。例如，代谢型谷氨酸（mGlu）受体激动剂（1S，3R）-1 - 氨基环戊烷 - 1,3 - 二羧酸（ACPD）已被证明可提高大鼠血清皮质酮水平。本研究旨在进一步明确哪些mGlu受体在HPA轴的调控中起重要作用。发现I组mGlu受体激动剂3,5 - 二羟基苯甘氨酸（DHPG）、1S，3R - ACPD和2 - 氯 - 5 - 羟基苯甘氨酸（CHPG），而非无活性的异构体1R，3S - ACPD，在雄性大鼠脑室内（i.c.v.）注射1小时后能剂量依赖性地提高血清皮质酮水平。相对效价为DHPG（EC50 = 520 nmol）> 1S，3R - ACPD（1.4 μmol）= CHPG（2.7 μmol）>> 1R，3S - ACPD（>> 3 μmol），这与I组（mGlu1/5）受体的激活情况一致。DHPG的作用持久，皮质酮水平显著升高至少持续3小时。同样，III组mGlu受体激动剂L - AP4（4 - 膦酰基 - 2 - 氨基丁酸）和L - SOP（丝氨酸 - O - 磷酸）在1小时时也能提高血清皮质酮水平。相比之下，mGlu II组选择性激动剂LY354740（10 mg/kg，腹腔注射）和II组拮抗剂LY341495的亚型选择性剂量（1 mg/kg，腹腔注射）并未显著提高血清皮质酮水平。鉴于I组激动剂的结果，令人惊讶的是，单独给予I组选择性拮抗剂和mGlu1选择性拮抗剂也会提高血清皮质酮水平。与激动剂一样，LY393675（一种mGlu1/5拮抗剂，EC50 = 20 nmol，i.c.v.）和LY367385（一种mGlu1拮抗剂，325 nmol，i.c.v.）引起的血清皮质酮升高呈剂量依赖性，且与它们对I组mGlu受体的相对亲和力一致。选择性mGlu5拮抗剂MPEP [2 - 甲基 - 6 - （苯乙炔基）吡啶]仅在高剂量（> 30 mg/kg，腹腔注射）时才会提高血清皮质酮水平。文中讨论了一种涉及下丘脑室旁核中GABA能中间神经元上高谷氨酸能张力的模型，作为这些结果的一种可能解释。
