Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia.
Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Mol Psychiatry. 2022 Dec;27(12):4861-4868. doi: 10.1038/s41380-022-01739-9. Epub 2022 Sep 1.
Trace amine-associated receptor 1 (TAAR1) has been recently identified as a target for the future antidepressant, antipsychotic, and anti-addiction drugs. Full (e.g. RO5256390) and partial (e.g. RO5263397) TAAR1 agonists showed antidepressant-, antipsychotic- and anti-addiction-like behavioral effects in rodents and primates. Acute RO5256390 suppressed, and RO5263397 stimulated serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) and dopamine neurons of the ventral tegmental area (VTA) in brain slices, suggesting that the behavioral effects of TAAR1 ligands involve 5-HT and dopamine. For more comprehensive testing of this hypothesis, we examined acute and chronic effects of RO5256390 and RO5263397 on monoamine neurons in in vivo conditions. Excitability of 5-HT neurons of the DRN, noradrenaline neurons of the locus coeruleus (LC), and dopamine neurons of the VTA was assessed using single-unit electrophysiology in anesthetized rats. For acute experiments, RO5256390 and RO5263397 were administered intravenously; neuronal excitability after RO5256390 and RO5263397 administration was compared to the basal activity of the same neuron. For chronic experiments, RO5256390 was administered orally for fourteen days prior to electrophysiological assessments. The neuronal excitability in RO5256390-treated rats was compared to vehicle-treated controls. We found that acute RO5256390 inhibited 5-HT and dopamine neurons. This effect of RO5256390 was reversed by the subsequent and prevented by the earlier administration of RO5263397. Acute RO5256390 and RO5263397 did not alter the excitability of LC noradrenaline neurons in a statistically significant way. Chronic RO5256390 increased excitability of 5-HT neurons of the DRN and dopamine neurons of the VTA. In conclusion, the putative antidepressant and antipsychotic effects of TAAR1 ligands might be mediated, at least in part, via the modulation of excitability of central 5-HT and dopamine neurons.
痕量胺相关受体 1（TAAR1）最近被确定为未来抗抑郁药、抗精神病药和抗成瘾药物的靶点。完全（例如 RO5256390）和部分（例如 RO5263397）TAAR1 激动剂在啮齿动物和灵长类动物中表现出抗抑郁、抗精神病和抗成瘾样行为效应。急性 RO5256390 抑制了脑切片中背侧中缝核（DRN）的 5-羟色胺（5-HT）神经元和腹侧被盖区（VTA）的多巴胺神经元，而 RO5263397 则刺激了这些神经元，这表明 TAAR1 配体的行为效应涉及 5-HT 和多巴胺。为了更全面地检验这一假设，我们在体内条件下研究了 RO5256390 和 RO5263397 对单胺能神经元的急性和慢性作用。在麻醉大鼠中使用单细胞电生理学评估 DRN 的 5-HT 神经元、蓝斑核（LC）的去甲肾上腺素神经元和 VTA 的多巴胺神经元的兴奋性。对于急性实验，RO5256390 和 RO5263397 静脉内给药；RO5256390 和 RO5263397 给药后神经元兴奋性与同一神经元的基础活性进行比较。对于慢性实验，RO5256390 口服给药 14 天，然后进行电生理评估。将 RO5256390 处理大鼠的神经元兴奋性与载体处理对照进行比较。我们发现，急性 RO5256390 抑制 5-HT 和多巴胺神经元。这种 RO5256390 的作用被随后给予的 RO5263397 逆转，并被预先给予 RO5263397 预防。急性 RO5256390 和 RO5263397 对 LC 去甲肾上腺素神经元的兴奋性没有统计学上的显著改变。慢性 RO5256390 增加了 DRN 5-HT 神经元和 VTA 多巴胺神经元的兴奋性。总之，TAAR1 配体的潜在抗抑郁和抗精神病作用可能至少部分通过调节中枢 5-HT 和多巴胺神经元的兴奋性来介导。
