The role of purinergic and dopaminergic systems on MK-801-induced antidepressant effects in zebrafish

Silva, Raquel Bohrer da; Siebel, Anna Maria; Bonan, Carla Denise

doi:10.1016/j.pbb.2015.05.005

Cited by 13 publications

(6 citation statements)

References 60 publications

(63 reference statements)

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“…Therefore, the present findings suggest that A 1 receptor activation might be another important downstream pathway in the actions of rapidly acting antidepressants. Of interest in this regard is a recent report that the potent noncompetitive NMDA receptor antagonist (1)-MK-801 might induce antidepressant-like effects in zebra fish through A 1 receptors (da Silva et al, 2015). It is noteworthy that the metabolomics analysis did not uncover mTOR as a potential target for either ketamine or LY3020371 despite reports of mTOR involvement (Li et al, 2010;Dwyer et al, 2012) and the blockade of effects of ketamine and LY3020371 reported here (Fig.…”

Section: Discussionmentioning

confidence: 58%

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

Witkin

Mitchell

Wafford

et al. 2017

J Pharmacol Exp Ther

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The ability of the -methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1,2,3,4,5,6)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.

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Section: Discussionmentioning

confidence: 58%

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

Witkin

Mitchell

Wafford

et al. 2017

J Pharmacol Exp Ther

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“…Zebrafish embryos/larvae have a functional DA system and they accordingly respond to a number of drugs including drugs of abuse (Buske and Gerlai, 2011; Kung et al, 2015; Levin et al, 2011; Suen et al, 2013). Furthermore, zebrafish has been used to study the antidepressant-like effects of MK-801, an NMDA receptor antagonist (da Silva et al, 2015). Our earlier studies demonstrated that exposure of embryos to 2 mM ketamine resulted in an internal exposure of ~8 µM (Trickler et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

Robinson

Dumas

Cuevas

et al. 2016

Neurotoxicology and Teratology

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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.

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“…For example, exposure to low doses of MK-801 (ranging from 2 to 20 M) has been reported to increase total distance traveled in adult zebrafish [13,17] and also in zebrafish larvae [3,18]. Conversely, other studies administering similar doses, in addition to much higher doses (up to 200 M), found no significant changes in the total distance traveled [19] or in locomotor activity quantified by number of crossings [12,14].…”

mentioning

confidence: 99%

“…Several studies measured locomotor activity of zebrafish during exposure to the drug [12,14,19]. In other studies, zebrafish were pre-treated with MK-801 (often in a small volume exposure chamber), and the total distance traveled was quantified subsequently when the zebrafish was placed in a larger novel tank or testing apparatus without continual administration of the drug [9,13,17,18]. In the current study, we investigate whether the inconsistent reports on the effects of MK-801 on locomotor activity are potentially due to such context-dependent variables.…”

mentioning

confidence: 99%

“…However, dopaminergic neurotransmission (e.g. dopamine synthesis and metabolism) has not been examined in zebrafish [9,13,17]. To investigate potential changes in the functioning of the dopaminergic system, we quantified the levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) from whole-brain tissue of zebrafish following exposure to MK-801.…”

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confidence: 99%

See 1 more Smart Citation

MK-801 increases locomotor activity in a context-dependent manner in zebrafish

Tran

Muraleetharan

Fulcher

et al. 2016

Behavioural Brain Research

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The role of purinergic and dopaminergic systems on MK-801-induced antidepressant effects in zebrafish

Cited by 13 publications

References 60 publications

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

MK-801 increases locomotor activity in a context-dependent manner in zebrafish

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