A Zebrafish Model of Neurotoxicity by Binge-Like Methamphetamine Exposure.

Juliette Bedrossiantz,Melissa Faria,Cristian Gómez-Canela,Demetrio Raldúa,Raul López-Arnau,Eva Prats,Marina Bellot,Pol Dominguez-García,Elena Escubedo

doi:10.3389/fphar.2021.770319

Abstract

Hyperthermia is a common confounding factor for assessing the neurotoxic effects of methamphetamine (METH) in mammalian models. The development of new models of methamphetamine neurotoxicity using vertebrate poikilothermic animals should allow to overcome this problem. The aim of the present study was to develop a zebrafish model of neurotoxicity by binge-like methamphetamine exposure. After an initial testing at 20 and 40 mg/L for 48 h, the later METH concentration was selected for developing the model and the effects on the brain monoaminergic profile, locomotor, anxiety-like and social behaviors as well as on the expression of key genes of the catecholaminergic system were determined. A concentration- and time-dependent decrease in the brain levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) was found in METH-exposed fish. A significant hyperactivity was found during the first hour of exposure, followed 3 h after by a positive geotaxis and negative scototaxis in the novel tank and in the light/dark paradigm, respectively. Moreover, the behavioral phenotype in the treated fish was consistent with social isolation. At transcriptional level, th1 and slc18a2 (vmat2) exhibited a significant increase after 3 h of exposure, whereas the expression of gfap, a marker of astroglial response to neuronal injury, was strongly increased after 48 h exposure. However, no evidences of oxidative stress were found in the brain of the treated fish. Altogether, this study demonstrates the suitability of the adult zebrafish as a model of METH-induced neurotoxicity and provides more information about the biochemical and behavioral consequences of METH abuse.

Highlights

Methamphetamine (METH) is a highly addictive psychostimulant drug affecting both the dopaminergic and serotonergic systems in the central nervous system (CNS) (Kobeissy et al, 2012)
A few recent studies have analyzed some of the addictive effects of METH in adult zebrafish (Mi et al, 2016; Zhu et al, 2017), information on the neurotoxic effects of the acute exposure to this stimulant drug is currently missing
METH levels determined in the brain of chronic human consumers are in the range 0.24–56.6 ng/mg brain tissue, and the distribution among the different brain areas seems quite homogeneous (Wilson et al, 1996; Kalasinsky et al, 2001; Moszczynska et al, 2004)

Summary

Introduction

Methamphetamine (METH) is a highly addictive psychostimulant drug affecting both the dopaminergic and serotonergic systems in the central nervous system (CNS) (Kobeissy et al, 2012). Some METH abusers binge on the drug for days in order to prolong euphoria (Shabani et al, 2019). Zebrafish Model of Methamphetamine Neurotoxicity (every 2 h), over several days (typically 1–3 days) This abuse pattern results in nearly steady-state plasma levels of METH during most of the binge period (Davidson et al, 2001; Shabani et al, 2019). Whereas central dopaminergic system seems to mediate the changes in mood, excitation level and motor movement, serotonergic system may contribute to the METH-related mood changes, psychosis, and aggressiveness (Albertson et al, 1999)

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Conclusion