Effect of antidepressants on circadian rhythms in fish: Insights and implications regarding the design of behavioural toxicity tests

Abstract

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) are widely prescribed for the treatment of depression and anxiety disorders. Consequently, these compounds are frequently identified in global waterways where they may pose a hazard to aquatic biota. Evidence demonstrates these compounds to be capable of influencing the behaviour of fish, but the relevance of many reported behavioural endpoints is unclear and the value of some findings has been questioned. Since these compounds act on neuroendocrine-mediated pathways in vertebrates, the present study explored how exposure to two representative SSRIs (fluoxetine and sertraline) and an SNRI (venlafaxine) affect circadian rhythms in fish. Male mosquitofish (Gambusia holbrooki) were exposed to 1, 10 and 100 μg/L concentrations of these compounds individually and when present as a full mixture, for a period of one week. Neither fluoxetine nor sertraline had an impact on diurnal activity patterns when fish were exposed to these compounds alone at any concentration, whereas venlafaxine significantly disrupted normal circadian rhythmicity but only at 100 μg/L. When fish were exposed to the full mixture, significantly altered diurnal activity patterns were rapidly observed at nominal concentrations of 1 and 100 μg/L, but there was no effect at 10 μg/L. This sort of non-monotonic dose relationship is not altogether unusual for fish exposed to antidepressants, but it poses a problem when attempting to evaluate potential risks to the aquatic environment. To evaluate the possibility for misinterpretation when collecting behavioural data over short temporal scales, the data for each day of the experiment was analysed separately. The outcomes demonstrate the importance of longer periods of data collection, which may be necessary to capture the full range of natural behavioural variability that exists both amongst and within individual fish. More importantly, these findings may help reveal why discrepancies are commonly being reported in the literature with regards behavioural effects in fish exposed to antidepressants. It is thus suggested that research be aimed at documenting behavioural variability in fish species used in toxicity testing, to establish guidelines for quality control and where possible inform the development of standardised methodologies so that behavioural analysis can be more appropriately applied to the broad field of aquatic toxicology.