Stress-related neuropsychiatric disorders are widespread, debilitating and often treatment-resistant illnesses that represent an urgent unmet biomedical problem. Animal models of these disorders are widely used to study stress pathogenesis. A more recent and historically less utilized model organism, the zebrafish (Danio rerio), is a valuable tool in stress neuroscience research. Utilizing the 5-week chronic unpredictable stress (CUS) model, here we examined brain transcriptomic profiles and complex dynamic behavioral stress responses, as well as neurochemical alterations in adult zebrafish and their correction by chronic antidepressant, fluoxetine, treatment. Overall, CUS induced complex neurochemical and behavioral alterations in zebrafish, including stable anxiety-like behaviors and serotonin metabolism deficits. Chronic fluoxetine (0.1 mg/L for 11 days) rescued most of the observed behavioral and neurochemical responses. Finally, whole-genome brain transcriptomic analyses revealed altered expression of various CNS genes (partially rescued by chronic fluoxetine), including inflammation-, ubiquitin- and arrestin-related genes. Collectively, this supports zebrafish as a valuable translational tool to study stress-related pathogenesis, whose anxiety and serotonergic deficits parallel rodent and clinical studies, and genomic analyses implicate neuroinflammation, structural neuronal remodeling and arrestin/ubiquitin pathways in both stress pathogenesis and its potential therapy.
Arecoline
is a naturally occurring psychoactive alkaloid from areca
(betel) nuts of the areca palm (Areca catechu) endemic
to South and Southeast Asia. A partial agonist of nicotinic and muscarinic
acetylcholine receptors, arecoline evokes multiple effects on the
central nervous system (CNS), including stimulation, alertness, elation,
and anxiolysis. Like nicotine, arecoline also evokes addiction and
withdrawal symptoms (upon discontinuation). The abuse of areca nuts
is widespread, with over 600 million users globally. The importance
of arecoline is further supported by its being the world’s
fourth most commonly used human psychoactive substance (after alcohol,
nicotine, and caffeine). Here, we discuss neuropharmacology, pharmacokinetics,
and metabolism of arecoline, as well as social and historical aspects
of its use and abuse. Paralleling clinical findings, we also evaluate
its effects in animal models and outline future clinical and preclinical
CNS research in this field.
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