title: Distinct effects of ketamine and acetyl L-carnitine on the dopamine system in zebrafish.
abstract: 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.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Robinson
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Dumas
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Elvis
authors.initials: E
authors.lastname: Cuevas
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: jyotshnabala.kanungo@fda.hhs.gov.
authors.forename: Jyotshna
authors.initials: J
authors.lastname: Kanungo
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000108:Acetylcarnitine / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006719:Homovanillic Acid / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
chemical_list: D000700:Analgesics; D012333:RNA, Messenger; D015102:3,4-Dihydroxyphenylacetic Acid; D007649:Ketamine; D000108:Acetylcarnitine; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D004298:Dopamine; D006719:Homovanillic Acid
keywords: Acetyl l-carnitine; Dopamine; Ketamine; MAO; Tyrosine hydroxylase; Zebrafish