Behavioral Study of 3-and 5-Halocytisine Derivatives in Zebrafish Using the Novel Tank Diving Test (NTT)

Anxiety is a serious mental disorder, and recent statistics have determined that 35.12% of the global population had an anxiety disorder during the COVID-19 pandemic. A mechanism associated with anxiolytic effects is related to nicotinic acetylcholine receptor (nAChR) agonists, principally acting on the & alpha;4 & beta;2 nAChR subtype. nAChRs are present in different animal models, including murine and teleosteos ones. Zebrafish has become an ideal animal model due to its high human genetic similarities (70%), giving it high versatility in different areas of study, among them in behavioral studies related to anxiety. The novel tank diving test (NTT) is one of the many paradigms used for studies on new drugs related to their anxiolytic effect. In this work, an adult zebrafish was used to determine the behavioral effects of 3- and 5-halocytisine derivatives, using the NTT at different doses. Our results show that substitution at position 3 by chlorine or bromine decreases the time spent by the fish at the bottom compared to the control. However, the 3-chloro derivative at higher doses increases the bottom dwelling time. In contrast, substitution at the 5 position increases bottom dwelling at all concentrations showing no anxiolytic effects in this model. Unexpected results were observed with the 5-chlorocytisine derivative, which at a concentration of 10 mg/L produced a significant decrease in bottom dwelling and showed high times of freezing. In conclusion, the 3-chloro and 3-bromo derivatives show an anxiolytic effect, the 3-chlorocytisine derivative being more potent than the 3-bromo derivative, with the lowest time at the bottom of the tank at 1mg/L. On the other hand, chlorine, and bromine at position 5 produce an opposite effect.

Automated summary

Anxiety is a serious mental disorder, and around 35.12% of the global population experienced anxiety during the COVID-19 pandemic. Anxiolytic effects can be achieved through the activation of α4β2 nicotinic acetylcholine receptors (nAChRs). Zebrafish, due to its high genetic similarity to humans (70%), has become an ideal animal model for studying anxiety-related behaviors. The novel tank diving test (NTT) is a commonly used paradigm to assess the anxiolytic effects of new drugs. This study found that 3-chloro and 3-bromo derivatives exhibited anxiolytic effects, while chlorine and bromine substitutions at position 5 had an opposite effect.