Antagonistic interaction between caffeine and ketamine in zebrafish: Implications for aquatic toxicity.
Zhenglu Wang, Jindong Xu, Wei Du
Environmental science and ecotechnology September 1, 2024 DOI: 10.1016/j.ese.2024.100437 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Pilot study Peer reviewed |
|---|---|
| Population | Zebrafish larvae |
| Interventions | Caffeine Ketamine |
| Dose | 2 mg L-1 of CF; 10-250 ng L-1 of KET |
| Duration | Seven-day recovery period |
| Topics | Ketamine Esketamine |
| Keywords | Antagonistic effect Caffeine Gabaergic synapse Systems toxicology Drug-interactions Aquatic-ecotoxicology |
| Citations | 6 |
| Key findings | Ketamine antagonizes the adverse effects of caffeine on zebrafish larvae by modulating the GABAergic synapse pathway, reducing hyperactivity, circadian rhythm disruption, and developmental abnormalities. |
Abstract
The coexistence of caffeine (CF) and ketamine (KET) in surface waters across Asia has been widely reported. Previous studies have implied that CF and KET may share a mechanism of action. However, the combined toxicity of these two chemicals on aquatic organisms remains unclear at environmental levels, and the underlying mechanisms are not well understood. Here we demonstrate that KET antagonizes the adverse effects of CF on zebrafish larvae by modulating the gamma-aminobutyric acid (GABA)ergic synapse pathway. Specifically, KET (10-250 ng L-1) ameliorates the locomotor hyperactivity and impaired circadian rhythms in zebrafish larvae induced by 2 mg L-1 of CF, showing a dose-dependent relationship. Additionally, the developmental abnormalities in zebrafish larvae exposed to CF are mitigated by KET, with an incidence rate reduced from 26.7% to 6.7%. The competition between CF and KET for binding sites on the GABA-A receptor (in situ and in silico) elucidates the antagonistic interactions between the two chemicals. Following a seven-day recovery period, the adverse outcomes of CF exposure persist in the fish, whereas the changes observed in the CF + KET groups are significantly alleviated, especially with KET at 10 ng L-1. Based on these results, it is imperative to further assess the environmental risks associated with CF and KET co-pollution. This pilot study underscores the utility of systems toxicology approaches in estimating the combined toxicity of environmental chemicals on aquatic organisms. Moreover, the nighttime behavioral functions of fish could serve as a sensitive biomarker for evaluating the toxicity of psychoactive substances.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 3
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Glutamate and GABA Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine Biological Psychiatry May 12, 2016
- A behavioral and molecular analysis of ketamine in zebrafish. Synapse February 2011