Centre for Human Drug Research, Leiden, The Netherlands.
Prog Neuropsychopharmacol Biol Psychiatry. 2010 Apr 16;34(3):486-91. doi: 10.1016/j.pnpbp.2010.01.019. Epub 2010 Feb 4.
Functional proton magnetic resonance spectroscopy (MRS) can be applied to measure pharmacodynamic effects of central nervous system (CNS)-active drugs. The serotonin precursor 5-hydroxytryptophan (5-HTP), administered together with carbidopa and granisetron to improve kinetics and reduce adverse effects, acutely enhances central serotonergic neurotransmission and induces hypothalamus-pituitary-adrenal-(HPA) axis activation. We studied the hypothalamic levels of glutamate/glutamine (Glx), choline (Chol), N-acetyl-aspartate (NAA) and creatine using 7-Tesla (7T) MRS, and adrenocorticotropic hormone (ACTH) and cortisol in peripheral blood, after the administration of the 5-HTP function test in healthy volunteers.
A randomized, double blind, placebo-controlled, two-way cross-over study was performed in 12 healthy males with a 7day wash-out period. After administration of the oral 5-HTP function test, ACTH and cortisol were measured over 4h and MRS scans at 7T were performed every 30min over 3h measuring Glx:Creatine, Chol:Creatine and NAA:Creatine ratios.
In the hypothalamus, the administration of 5-HTP had no effect on the average Glx, Chol or NAA levels over 180min but induced a significant decrease of Glx at 60min on post-hoc analysis. 5-HTP-induced significant ACTH release reaching an E(max) of 60.2ng/L at 80min followed by cortisol with an E(max) of 246.4ng/mL at 110min.
The reduction in hypothalamic Glx levels after serotonergic stimulation is compatible with activation of excitatory neurons in this region, which is expected to cause depletion of local glutamate stores. The hypothalamic MRS-response reached its maximum prior to subsequent increases of ACTH and cortisol, which support the functional relevance of hypothalamic Glx-depletion for activation of the HPA-axis. This exploratory study shows that MRS is capable of detecting neuronal activation following functional stimulation of a targeted brain area.
功能质子磁共振波谱（MRS）可用于测量中枢神经系统（CNS）活性药物的药效动力学效应。5-羟色氨酸（5-HTP）是一种血清素前体，与卡比多巴和格拉司琼联合使用可改善动力学并减少不良反应，可急性增强中枢血清素能神经传递，并诱导下丘脑-垂体-肾上腺轴（HPA 轴）激活。我们使用 7 特斯拉（7T）MRS 研究了健康志愿者中 5-HTP 功能测试后下丘脑的谷氨酸/谷氨酰胺（Glx）、胆碱（Chol）、N-乙酰天门冬氨酸（NAA）和肌酸水平，以及外周血中的促肾上腺皮质激素（ACTH）和皮质醇。
在 12 名健康男性中进行了一项随机、双盲、安慰剂对照、双向交叉研究，洗脱期为 7 天。口服 5-HTP 功能测试后，在 4 小时内测量 ACTH 和皮质醇，并在 3 小时内每 30 分钟进行一次 7T MRS 扫描，测量 Glx：Creatine、Chol：Creatine 和 NAA：Creatine 比值。
在 180 分钟内，5-HTP 给药对下丘脑平均 Glx、Chol 或 NAA 水平没有影响，但在事后分析中，60 分钟时 Glx 显著降低。5-HTP 诱导的 ACTH 释放显著，80 分钟时达到 60.2ng/L 的 E(max)，随后皮质醇在 110 分钟时达到 246.4ng/mL 的 E(max)。
血清素刺激后下丘脑 Glx 水平的降低与该区域兴奋性神经元的激活一致，预计会导致局部谷氨酸储存耗尽。下丘脑 MRS 反应在随后的 ACTH 和皮质醇增加之前达到最大值，这支持了下丘脑 Glx 耗竭对 HPA 轴激活的功能相关性。这项探索性研究表明，MRS 能够检测到靶向脑区功能刺激后的神经元激活。
