Robinson Bonnie L, Dumas Melanie, Cuevas Elvis, Gu Qiang, Paule Merle G, Ali Syed F, Kanungo Jyotshna
Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
Neurotoxicol Teratol. 2016 Mar-Apr;54:52-60. doi: 10.1016/j.ntt.2016.02.004. Epub 2016 Feb 16.
Ketamine, a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1-0.3 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression.
氯胺酮是一种非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，常用于儿科麻醉。我们之前已经表明，乙酰左旋肉碱（ALCAR）可预防斑马鱼胚胎中的氯胺酮毒性。在哺乳动物中，已知氯胺酮可调节多巴胺能系统。NMDA受体拮抗剂被认为是有前景的抗抑郁药，但其确切的作用机制尚不清楚。在此，我们测量了在存在和不存在0.5 mM ALCAR的情况下，暴露于氯胺酮的斑马鱼胚胎中多巴胺（DA）及其代谢产物3,4-二羟基苯乙酸（DOPAC）和高香草酸（HVA）的水平。较低剂量（0.1-0.3 mM）的氯胺酮在受精后52小时的胚胎中处理24小时，未导致DA、DOPAC或HVA水平发生显著变化。在这些胚胎中，酪氨酸羟化酶（TH）mRNA表达保持不变。然而，2 mM氯胺酮（胚胎内部暴露水平相当于人类麻醉血浆浓度）显著降低了DA水平和TH mRNA，表明DA合成受到不利影响。在存在或不存在2 mM氯胺酮的情况下，ALCAR对DA水平和TH mRNA显示出相似的影响，但与对照组相比，DOPAC水平升高。ALCAR逆转了2 mM氯胺酮诱导的HVA水平降低。单独使用ALCAR时，编码DA代谢酶单胺氧化酶（MAO）和儿茶酚-O-甲基转移酶（COMT）的基因表达未受影响。然而，氯胺酮改变了MAO mRNA表达，但0.1 mM剂量除外。在2 mM氯胺酮处理组中，COMT转录本减少。氯胺酮和ALCAR对DA系统的这些不同影响可能有助于揭示氯胺酮如何作为抗抑郁药起作用的机制，特别是在不影响DA代谢和抑制MAO基因表达的亚麻醉剂量下。
