Dopamine Release Impairments Accompany Locomotor and Cognitive Deficiencies in Rotenone-Treated Parkinson’s Disease Model Zebrafish

Abstract

In this work, we carried out neurochemical and behavioral analysis of zebrafish (Danio rerio) treated with rotenone, an agent used to chemically induce a syndrome resembling Parkinson's disease (PD). Dopamine release, measured with fast-scan cyclic voltammetry (FSCV) at carbon-fiber electrodes in acutely harvested whole brains, was about 30% of that found in controls. Uptake, represented by the first order rate constant (k) and the half-life (t 1/2 ) determined by nonlinear regression modeling of the stimulated release plots, was also diminished. Behavioral analysis revealed that rotenone treatment increased the time required for zebrafish to reach a reward within a maze by more than 50% and caused fish to select the wrong pathway, suggesting that latent learning was impaired. Additionally, zebrafish treated with rotenone suffered from diminished locomotor activity, swimming shorter distances with lower mean velocity and acceleration. Thus, the neurochemical and behavioral approaches, as applied, were able to resolve rotenone-induced differences in key parameters. This approach may be effective for screening therapies in this and other models of neurodegeneration.

Monoterpenoid Epoxidiol Ameliorates the Pathological Phenotypes of the Rotenone-Induced Parkinson’s Disease Model by Alleviating Mitochondrial Dysfunction

“…It is used both to elucidate the mechanisms underlying the death of dopaminergic cells and to study new potential neuroprotective agents [ 20 , 21 , 22 , 23 ]. This is due to its involvement in many pathological pathways that mediate the death of dopaminergic neurons [ 24 , 25 , 26 ], the ability to reproduce both motor [ 27 , 28 ] and non-motor symptoms of parkinsonism [ 29 , 30 , 31 ], as well as an extremely high lipophilicity [ 32 ], which allows it to penetrate easily the blood–brain barrier. Figure 2 shows the mechanisms of rotenone action that cause neuropathological signs, as well as motor and non-motor symptoms.…”

Imaging Approaches to Investigate Pathophysiological Mechanisms of Brain Disease in Zebrafish

“…Jarosova and colleagues [ 139 ] employed an adult zebrafish pharmacological model of Alzheimer’s disease (okadaic acid) showing impaired learning and decreased motivation in reaching the goal chamber in an alternative maze. This peculiar type of maze was also employed by the same group to describe the locomotor and cognitive deficiencies in a rotenone Parkinson’s disease model in adult zebrafish [ 140 ] ( Figure 3 e). Cleal and colleagues [ 141 ] tested 24-month-old zebrafish performance in a Y-maze, demonstrating that the aging-related cognitive decline is related to dopaminergic activity.…”

“…Plots show an overall reduction in locomotor activity in treated animals with respect to both untreated and vehicle fish. Figure reprinted with permission from [ 140 ] © American Chemical Society. ( f ) Representative 3D tracking of adult zebrafish exposed to either anxiogenic (first plot from left) or anxiolytic (second plot from left) treatments.…”

Neuroprotective effects of Neurotrophin-3 in MPTP-induced zebrafish Parkinson’s disease model

“…Zebrafish has particularly found prominence as a PD model, either through neurotoxin induction or genetic modifications. Neurotoxins that have been previously used, such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone and paraquat have been shown to mimic the PD features in zebrafish, especially the neurobehavioral changes and the degeneration of the dopaminergic neuron ( Benvenutti et al, 2018 ; Bashirzade et al, 2022 ; Hettiarachchi et al, 2022 ; Kim et al, 2022 ). While genetic modifications hold promise, the resulting phenotypic variations can be quite diverse ( Prabhudesai et al, 2016 ; Sheng et al, 2018 ; Van Laar et al, 2020 ).…”