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 α4ß2 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.

Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish.

Zebrafish is becoming a popular animal model in neuropharmacology and drug discovery, mainly due to its ease of handling and low costs involved in maintenance and experimental work. This animal displays a series of complex behaviours that makes it useful for assessing the effects of psychoactive drugs. Here, adult zebrafish were used for assessment of the anxiolytic and anti-addictive properties of UFR2709, a nicotinic receptor (nAChR) antagonist, using two behavioural paradigms to test for addiction, the novel tank diving test to assess anxiety and the conditioned place preference (CPP). Furthermore, the expression of nAChR subunits α4 and α7 was measured in the zebrafish brain. The results show that UFR2709 exhibits an anxiolytic effect on zebrafish and blocks the effect evoked by nicotine on CPP. Moreover, UFR2709 significantly decreased the expression of α4 nicotinic receptor subunit. This indicates that UFR2709 might be a useful drug for the treatment of nicotine addiction.