Sustained Anxiolytic-Like Effects of N-Acetylcysteine in Zebrafish Subjected to Unpredictable Chronic Stress

Introduction: Mental disorders such as anxiety and depression are highly prevalent in today's society, representing a public health issue that causes deleterious effects on individuals and healthcare systems. Despite their significance, there are currently no highly effective, sustained-acting medications with minimal adverse effects available, highlighting the need for new pharmacological options. Objective: To investigate the sustained effect of N-acetylcysteine (NAC) on behavioral parameters in zebrafish subjected to an unpredictable chronic stress (UCS) protocol. Methodology: Eighty zebrafish were allocated into eight experimental groups, with 10 animals each. Four of the groups were subjected to UCS (+), and four were not (-). Each of these four groups was exposed to either N-acetylcysteine (NAC, 10 mg/L, 20 min), Fluoxetine (FLU, 10 mg/L, 20 min), Ketamine (KET, 20 mg/L, 20 min), or a control solution (CTRL, water, 20 min). During the first seven days, the animals were exposed to the UCS protocol. On the 7th day, they received their respective pharmacological treatments (CTRL, NAC, FLU, or KET). After 24 hours of treatment exposure (day 8), the animals were subjected to the novel tank test, where the following parameters were evaluated: distance traveled (m); number of crossings; and time spent in the upper and lower areas (s). Results: UCS reduced the number of crossings and time spent in the upper area and increased the time spent in the lower area. All treatments (NAC, FLU, and KET) were able to mitigate the anxiogenic-like effect induced by UCS. Additionally, FLU exhibited anxiolytic-like behavior in animals not subjected to UCS. Conclusions: Considering the sustained effect of NAC in reversing the anxiogenic effect induced by stress, its good safety and tolerability profile in humans, as well as its low cost, this study reinforces the applicability of NAC in stress-related neuropsychiatric disorders.