Ketamine acutely impairs memory consolidation and repeated exposure promotes stereotyped behavior without changing anxiety- and aggression-like parameters in adult zebrafish.

Abstract

Ketamine is a dissociative anesthetic in human and veterinary clinic, as well as an abuse drug that acts on several neurotransmitter systems. The use of alternative animal models, such as zebrafish, is emerging to study the effects of drugs on neurobehavioral responses. Here, we evaluated the effects of ketamine on memory consolidation (acute protocol), as well as on anxiety-, aggressive-like behavior, and whole-body cortisol levels in adult zebrafish after a repeated exposure. For the acute protocol, fish were tested in the inhibitory avoidance task (training and testing with 24-hour intervals). Immediately after the training session, fish were exposed to ketamine (0, 2, 20, or 40 mg/L) for 20 min. The exploratory activity was also measured 24 h after acute exposure to exclude the influence of impaired locomotion on memory performance. For the repeated exposure, animals were exposed to the same concentrations of ketamine for 20 min (7 days). After the last exposure (24 h later), anxiety- and aggression-like behaviors were quantified in the novel tank and mirror-induced aggression tests, respectively, as well as whole-body cortisol levels measurements were performed. The higher ketamine concentration tested (40 mg/L) acutely induced a slight memory impairment in the inhibitory avoidance task without changing locomotion and anxiety-like behaviors. Although locomotion, anxiety-, aggressive-like behaviors, and whole-body cortisol levels did not change after repeated exposure, 40 mg/L ketamine increased circling behavior. Overall, our data reinforce that ketamine acutely affects multiple behavioral domains in zebrafish, in which repeated ketamine exposure elicits stereotyped behavior, without changing locomotion, aggression, and anxiety/stress-like parameters.