PUBLICATION
Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish
- Authors
- Robinson, B.L., Dumas, M., Cuevas, E., Gu, Q., Paule, M.G., Ali, S.F., Kanungo, J.
- ID
- ZDB-PUB-160224-13
- Date
- 2016
- Source
- Neurotoxicology and teratology 54: 52-60 (Journal)
- Registered Authors
- Keywords
- Acetyl l-carnitine, Dopamine, Ketamine, MAO, Tyrosine hydroxylase, Zebrafish
- MeSH Terms
-
- 3,4-Dihydroxyphenylacetic Acid/metabolism
- Acetylcarnitine/pharmacology*
- Analgesics/pharmacology*
- Animals
- Catechol O-Methyltransferase/genetics
- Catechol O-Methyltransferase/metabolism
- Dopamine/metabolism*
- Dose-Response Relationship, Drug
- Drug Interactions
- Embryo, Mammalian/drug effects
- Female
- Gene Expression Regulation, Developmental/drug effects*
- Homovanillic Acid/metabolism
- Ketamine/pharmacology*
- Male
- Monoamine Oxidase/genetics
- Monoamine Oxidase/metabolism
- RNA, Messenger/metabolism
- Tyrosine 3-Monooxygenase/genetics
- Tyrosine 3-Monooxygenase/metabolism
- Zebrafish
- PubMed
- 26898327 Full text @ Neurotoxicol. Teratol.
Citation
Robinson, B.L., Dumas, M., Cuevas, E., Gu, Q., Paule, M.G., Ali, S.F., Kanungo, J. (2016) Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish. Neurotoxicology and teratology. 54:52-60.
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 0.5mM ALCAR. Ketamine, at lower doses (0.1-0.3mM), did not produce significant changes in DA, DOPAC or HVA levels in 52h post-fertilization embryos treated for 24h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2mM 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 2mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2mM 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 0.1mM dose. COMT transcripts were reduced in the 2mM 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping