Modulation of behavioral and neurochemical responses of adult zebrafish by fluoxetine, eicosapentaenoic acid and lipopolysaccharide in the prolonged chronic unpredictable stress model

Abstract

Long-term recurrent stress is a common cause of neuropsychiatric disorders. Animal models are widely used to study the pathogenesis of stress-related psychiatric disorders. The zebrafish (Danio rerio) is emerging as a powerful tool to study chronic stress and its mechanisms. Here, we developed a prolonged 11-week chronic unpredictable stress (PCUS) model in zebrafish to more fully mimic chronic stress in human populations. We also examined behavioral and neurochemical alterations in zebrafish, and attempted to modulate these states by 3-week treatment with an antidepressant fluoxetine, a neuroprotective omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA), a pro-inflammatory endotoxin lipopolysaccharide (LPS), and their combinations. Overall, PCUS induced severe anxiety and elevated norepinephrine levels, whereas fluoxetine (alone or combined with other agents) corrected most of these behavioral deficits. While EPA and LPS alone had little effects on the zebrafish PCUS-induced anxiety behavior, both fluoxetine (alone or in combination) and EPA restored norepinephrine levels, whereas LPS + EPA increased dopamine levels. As these data support the validity of PCUS as an effective tool to study stress-related pathologies in zebrafish, further research is needed into the ability of various conventional and novel treatments to modulate behavioral and neurochemical biomarkers of chronic stress in this model organism.

Effects of chronic exposure to fluoxetine, eicosapentaenoic acid, and lipopolysaccharide on behavior and hippocampal transcriptome in the rat model of prolonged chronic unpredictable stress

“…This profile also parallels fluoxetine effects in other rodent stress studies, including the modulation of anxiety in various shorter CUS protocols 51, 106-108 . Interestingly, fluoxetine+LPS unexpectedly produced robust anxiolytic effect on rat OF rearing (vs. stressed group) and open arm exploration in EPMT, but increased freezing duration in both tests, resembling hypolocomotor profile reported for this combination in zebrafish PCUS model 38 .…”

“…The present study, for the first time, applied clinically relevant PCUS model in rats (based on our recently developed zebrafish PCUS model 38 ) and characterized a wide range of behavioral and transcriptomic responses in stressed and drug-treated rats. The 12-week PCUS protocol aimed to recapitulate in rats pronounced and stable behavioral and molecular clinical phenotypes induced by chronic stress, and consistent with overt alterations in zebrafish behavior and neurochemistry 38 , hence strongly supporting further cross-species translation between stress models.…”

“…The present study, for the first time, applied clinically relevant PCUS model in rats (based on our recently developed zebrafish PCUS model 38 ) and characterized a wide range of behavioral and transcriptomic responses in stressed and drug-treated rats. The 12-week PCUS protocol aimed to recapitulate in rats pronounced and stable behavioral and molecular clinical phenotypes induced by chronic stress, and consistent with overt alterations in zebrafish behavior and neurochemistry 38 , hence strongly supporting further cross-species translation between stress models. The present study also explored potential pharmacological and dietary therapies in the PCUS model, including both widely used conventional antidepressant (fluoxetine) and putative novel (EPA) anti-stress treatments, as well as the combination of PCUS with a pro-inflammatory agent LPS that may exacerbate PCUS effects.…”

“…Rats were administered 0.5 mL distilled water containing 5 mg/kg fluoxetine using oral syringes. The duration of treatment, its dose and route of administration were selected based on the previous studies in stress-related models 38, 53 .…”

Pharmacological characterization of a novel putative nootropic beta-alanine derivative, MB-005, in adult zebrafish

“…The novel tank test represented a rectangular 2 L plastic tank (20 height × 20 length × 5 width cm) filled with fresh facility water and divided into two halves (top and bottom) by a virtual horizontal line, as in Demin et al (2021). For behavioral testing, fish were individually placed in the novel tank test for 5 min, scoring distance (m), velocity (m/s), frequency and duration (s) of highly mobile (set at > 80% of average mobility per trial), and immobile (set at < 20% of average mobility per trial) states, as well as the frequency, duration (s) and latency (s) to enter the top half of the tank.…”