Acute MK-801 induces hyperactivity and changes spatio-temporal exploratory dynamics without disrupting homebase retention in adult zebrafish.

The N-methyl-D-aspartate receptor (NMDAR) antagonist dizocilpine (MK-801) modulates locomotor functions and disrupts cognitive and spatial processes, making it useful for examining pharmacologically-induced behavioral phenotypes that mimic schizophrenia. Here, we investigated the impact of MK-801 on spatio-temporal exploratory dynamics in adult zebrafish, focusing on homebase behavior in the open field test (OFT). In Experiment 1, zebrafish received an intraperitoneal (i.p.) injection of saline or MK-801 (2.0 mg/kg), followed by a 15-min absorption period prior to a 30-min OFT. Experiment 2 involved an initial 30-min OFT, immediate saline or MK-801 (2.0 mg/kg), i.p. administration, and a retrial in the OFT 24 h later. Overall, MK-801 induced hyperactivity and stereotypy in Experiment 1. Although zebrafish were able to establish a homebase as a functionally relevant spatial reference, notable alterations in homebase-related behaviors were observed. Experiment 2 explored the homebase conservation across repeated OFT sessions, revealing that despite subtle changes in overall exploration and homebase occupancy, both groups demonstrated significant homebase conservation and reduced thigmotaxis in the retrial. An inhibitory avoidance task was also performed to confirm the amnesic effects of MK-801 on zebrafish (Experiment 3), revealing impaired aversive memory consolidation. Our novel findings indicate that while MK-801 altered movement patterns and disrupted aversive memory, zebrafish core spatial behaviors remained intact, highlighting the adaptive value of homebase as a conserved spatial strategy. Collectively, this work further supports the utility of zebrafish models for studying how pharmacological modulations of NMDAR affect spatial orientation and exploratory behavior, with translational relevance to neuropsychiatric diseases.