Department of Neurology and Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Department of Pharmaceutical Biosciences, Medical Mass Spectrometry Imaging, Uppsala University, Uppsala, Sweden.
Biol Psychiatry. 2021 Jul 1;90(1):16-27. doi: 10.1016/j.biopsych.2020.12.008. Epub 2020 Dec 19.
Monoamine oxidase inhibitors (MAOIs) exert therapeutic actions by elevating extracellular levels of monoamines in the brain. Irreversible MAOIs cause serious hypertensive crises owing to peripheral accumulation of tyramine, but the role of tyramine in the central effects of MAOIs remains elusive, an issue addressed herein. To achieve robust inhibition of MAOA/B, the clinically used antidepressant tranylcypromine (TCP) was employed.
Behavioral, histological, mass spectrometry imaging, and biosensor-mediated measures of glutamate were conducted with MAOIs in wild-type and TAAR1-knockout (KO) mice.
Both antidepressant and locomotion responses to TCP were enhanced in TAAR1-KO mice. A recently developed fluoromethylpyridinium-based mass spectrometry imaging method revealed robust accumulation of striatal tyramine on TCP administration. Furthermore, tyramine accumulation was higher in TAAR1-KO versus wild-type mice, suggesting a negative feedback mechanism for TAAR1 in sensing tyramine levels. Combined histoenzymological and immunohistological studies revealed hitherto unknown TAAR1 localization in brain areas projecting to the substantia nigra/ventral tegmental area. Using an enzyme-based biosensor technology, we found that both TCP and tyramine reduced glutamate release in the substantia nigra in wild-type but not in TAAR1-KO mice. Moreover, glutamate measures in freely moving animals treated with TCP demonstrated that TAAR1 prevents glutamate accumulation in the substantia nigra during hyperlocomotive states.
These observations suggest that tyramine, in interaction with glutamate, is involved in centrally mediated behavioral, transcriptional, and neurochemical effects of MAOIs.
单胺氧化酶抑制剂（MAOIs）通过提高大脑中单胺类物质的细胞外水平发挥治疗作用。由于外周酪氨酸的积累，不可逆的 MAOIs 会导致严重的高血压危象，但酪氨酸在 MAOIs 中枢作用中的作用仍不清楚，本文对此进行了探讨。为了实现 MAOA/B 的有效抑制，临床上使用的抗抑郁药反苯环丙胺（TCP）被采用。
使用 MAOIs 在野生型和 TAAR1 敲除（KO）小鼠中进行行为学、组织学、质谱成像和谷氨酸生物传感器测量。
TCP 对 TAAR1-KO 小鼠的抗抑郁和运动反应均增强。最近开发的基于氟甲基吡啶鎓的质谱成像方法显示，TCP 给药后纹状体酪氨酸积累明显。此外，TAAR1-KO 小鼠中的酪氨酸积累高于野生型小鼠，提示 TAAR1 存在一种负反馈机制来感知酪氨酸水平。联合组织化学和免疫组织化学研究揭示了 TAAR1 在投射到黑质/腹侧被盖区的脑区中的未知定位。使用基于酶的生物传感器技术，我们发现 TCP 和酪氨酸均降低了野生型小鼠中黑质中的谷氨酸释放，但在 TAAR1-KO 小鼠中则没有。此外，用 TCP 处理的自由活动动物的谷氨酸测量结果表明，TAAR1 可防止在 Hyperlocomotive 状态下黑质中谷氨酸的积累。
这些观察结果表明，在中枢介导的 MAOIs 的行为、转录和神经化学作用中，酪氨酸与谷氨酸相互作用。
