Ketamine modulates aggressive behavior in adult zebrafish

Michelotti, Paula; Quadros, Vanessa A.; Pereira, Maria Estér

doi:10.1016/j.neulet.2018.08.009

Cited by 32 publications

(21 citation statements)

References 37 publications

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“…Interestingly, pharmacological studies revealed high correlation with regard to the ability of larval and adult zebrafish to mimic positive SCZ symptoms. For example, ketamine [65,66] and MK-801 (also called dizocilpine) [54, 67] induce a robust increase in locomotion. Moreover, d-amphetamine or D 2 receptor agonists elicit the same locomotor response in adult zebrafish [68,69] as in rodents [70][71][72][73][74].…”

Section: Discussionmentioning

confidence: 99%

Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?

et al. 2020

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Persons with certain single nucleotide polymorphisms (SNPs) in the CACNA1D gene (encoding voltage-gated calcium channel subunit alpha 1-D) have increased risk of developing neuropsychiatric disorders such as bipolar, schizophrenia and autism. The molecular consequences of SNPs on gene expression and protein function are not well understood. Thus, the use of animal models to determine genotype-phenotype correlations is critical to understanding disease pathogenesis. Here, we describe the behavioural changes in larval zebrafish carrying an essential splice site mutation (sa17298) in cacna1da. Heterozygous mutation resulted in 50% reduction of splice variants 201 and 202 (haploinsufficiency), while homozygosity increased transcript levels of variant 201 above wild type (WT; gain-of-function, GOF). Due to low homozygote viability, we focused primarily on performing the phenotypic analysis on heterozygotes. Indeed, cacna1dasa17298/WT larvae displayed hyperlocomotion—a behaviour characterised in zebrafish as a surrogate phenotype for epilepsy, anxiety or psychosis-like behaviour. Follow-up tests ruled out anxiety or seizures, however, as neither thigmotaxis defects nor epileptiform-like discharges in larval brains were observed. We therefore focused on testing for potential “psychosis-like” behaviour by assaying cacna1dasa17298/WT larval locomotor activity under constant light, during light-dark transition and in startle response to dark flashes. Furthermore, exposure of larvae to the antipsychotics, risperidone and haloperidol reversed cacna1da-induced hyperactivity to WT levels while valproate decreased but did not reverse hyperactivity. Together, these findings demonstrate that cacna1da haploinsufficiency induces behaviours in larval zebrafish analogous to those observed in rodent models of psychosis. Future studies on homozygous mutants will determine how cacna1d GOF alters behaviour in this context.

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Section: Discussionmentioning

confidence: 99%

Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?

et al. 2020

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“…However, there are lack of studies about anti-aggressive effect of ketamine to rodent. Recently, one study reported lower sub-anesthetic concentrations (2 mg/L) increase aggression towards mirror, higher ketamine concentrations (20 mg/L and 40 mg/L) elicit stereotypic behaviors and reduce aggression for adult zebrafish [3]. Another study showed acute ketamine (7.5 and 10.0 mg/kg) suppressed aggressive performance in both control group and in historically alcohol-treated group of adult mice (PND 8 weeks) [26].…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies have assessed the therapeutic effects of ketamine, demonstrating its antidepressant and anxiolytic effects in humans as well as in rodents [2]. However, there are lack of studies about therapeutic effects of ketamine on aggression [3].…”

Section: Introductionmentioning

confidence: 99%

Chronic administration of ketamine ameliorates the anxiety- and aggressive-like behavior in adolescent mice induced by neonatal maternal separation

Shin

Baek

Han

et al. 2019

Korean J Physiol Pharmacol

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Ketamine has long been used as an anesthetic agent. However, ketamine use is associated with numerous side effects, including flashbacks, amnesia, delirium, and aggressive or violent behavior. Ketamine has also been abused as a cocktail with ecstasy, cocaine, and methamphetamine. Several studies have investigated therapeutic applications of ketamine, demonstrating its antidepressant and anxiolytic effects in both humans and rodents. We recently reported that neonatal maternal separation causes enhanced anxiety- and aggressive-like behaviors in adolescent. In the present study, we evaluated how acute and chronic ketamine administration affected the behavioral consequences of neonatal maternal separation in adolescent mice. Litters were separated from dams for 4 hours per day for 19 days beginning after weaning. Upon reaching adolescence (post-natal day 35–49), mice were acutely (single injection) or chronically (7 daily injections) treated with a sub-anesthetic dose (15 mg/kg) of ketamine. At least 1 h after administration of ketamine, mice were subjected to open-field, elevated-plus maze, and resident-intruder tests. We found that acute ketamine treatment reduced locomotor activity. In contrast, chronic ketamine treatment decreased anxiety, as evidenced by increased time spent on open arms in the elevated-plus maze, and remarkably reduced the number and duration of attacks. In conclusion, the present study suggests that ketamine has potential for the treatment of anxiety and aggressive or violent behaviors.

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“…Drug-induced stereotypic behaviors are not well characterized in zebrafish, but some authors suggest they may be displayed as altered rotation movements (Michelotti et al, 2018). To date, only a few studies explored the effects of MK-801 on stereotypy-related behaviors in zebrafish, and there is no study with AMPH.…”

Section: Discussionmentioning

confidence: 99%

How do zebrafish respond to MK-801 and amphetamine? Relevance for assessing schizophrenia-relevant endophenotypes in alternative model organisms

Benvenutti

Gallas‐Lopes

Sachett

et al. 2020

Preprint

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Background and Purpose: Schizophrenia pathophysiology has been associated with dopaminergic hyperactivity, loss of parvalbumin-positive GABAergic interneurons, NMDA receptor hypofunction, and redox dysregulation. Most behavioral assays and animal models to study this condition were developed in rodents, leaving room for species-specific biases that could be avoided by cross-species approaches. As MK-801 and amphetamine are largely used in mice and rats to mimic schizophrenia features, this study aimed to investigate the effects of these drugs in zebrafish. Experimental Approach: Adult zebrafish were exposed to MK-801 (1, 5, and 10 uM) or amphetamine (0.625, 2.5, and 10 mg.L-1) and observed in paradigms of locomotor activity and social behavior. Oxidative parameters relevant to schizophrenia were quantified in brain tissue. Key Results: MK-801 disrupted social interaction, an effect that resembles the negative symptoms of schizophrenia. It also altered locomotion in a context-dependent manner, with hyperactivity when fish were tested in the presence of social cues and hypoactivity when tested alone. On the other hand, exposure to amphetamine was devoid of effects on locomotion and social behavior, while increased lipid peroxidation in the brain. Conclusion and Implications: Key outcomes induced by MK-801 in rodents were replicated in zebrafish, which suggests this species is suitable as an alternative model animal to study psychotic disorders. More studies are necessary to further develop preclinical paradigms with this species and ultimately optimize the screening of potential novel treatments.

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Ketamine modulates aggressive behavior in adult zebrafish

Cited by 32 publications

References 37 publications

Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?

Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?

Chronic administration of ketamine ameliorates the anxiety- and aggressive-like behavior in adolescent mice induced by neonatal maternal separation

How do zebrafish respond to MK-801 and amphetamine? Relevance for assessing schizophrenia-relevant endophenotypes in alternative model organisms

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