The Behavioral and Pharmacological Actions of NMDA Receptor Antagonism are Conserved in Zebrafish Larvae

Abstract

Dizocilpine maleate (MK-801) is one of several NMDA receptor antagonists that is widely used to pharmacologically model the symptoms of psychosis and schizophrenia in animals. MK-801 elicits behaviors in adult zebrafish (Danio rerio) that are phenotypically consistent with behaviors observed in humans and rodents exposed to tbhe drug. However, the molecular and cellular processes that mediate the psychotomimetic, cognitive and locomotive behaviors of MK-801 are unclear. We exposed zebrafish larvae to MK-801 to assess their merit as a model organism to elucidate the behavioral effects of NMDA receptor blockade. Zebrafish larvae were acutely immersed in MK-801 to assess the effect on spontaneous swimming. MK-801 caused a time-and dose-dependent increase in larval swim speed, and the peak response (a five-fold increase in swim speed) was evoked by a three h exposure to a 20 uM dose. Zebrafish larvae did not exhibit sensitivity to the locomotor effects of MK-801 until 5 dpf, suggesting a critical role for developmental in sensitivity to the drug. Exposure to the low potency NMDA antagonist, memantine, did not alter the swim speed of zebrafish larvae. Co-immersion in D 1 or D 2 dopamine receptor antagonists did not disrupt the time course or magnitude of the increase in swim speed, suggesting dopaminergic signaling is not required for the locomotor actions of MK-801. Our findings of the behavioral actions of MK-801 in zebrafish larvae are consistent with previous observations in mammals and imply that the physiological, cellular and molecular processes disrupted by MK-801 are conserved in zebrafish larvae. These data suggest that the zebrafish larvae is a valid and useful model to elucidate neurobehavioral aspects of NMDA receptor antagonism and may provide insight to the neurobiology of psychosis and schizophrenia.

Effects of Pregnanolone Glutamate and Its Metabolites on GABAA and NMDA Receptors and Zebrafish Behavior

“…It has been shown earlier that certain pregnane steroids induce rapid sedation and anesthesia in rodents by a mechanism that was later associated with the enhancement of responses mediated by GABARs . Ketamine, a selective NMDAR inhibitor, has similar effects, that include dissociative anesthesia, pain relief, sedation, and amnesia. − Incomplete inhibition of spontaneous zebrafish locomotion was reported earlier for MK-801, a compound with a similar mode of action at the NMDAR as ketamine. ,− Inhibition of locomotion is also observed in zebrafish with knockouts of both paralogues the obligatory GluN1 subunit of the NMDAR . Thus, while it is clear that neurosteroids with modulatory action at GABARs and NMDARs can profoundly influence CNS function, further research is needed to better understand how individual steroids and their metabolites act in concert to alter the balance of excitation and inhibition in neural circuits, with clinically relevant consequences for behavior.…”

“… 76 − 79 Incomplete inhibition of spontaneous zebrafish locomotion was reported earlier for MK-801, a compound with a similar mode of action at the NMDAR as ketamine. 76 , 80 − 82 Inhibition of locomotion is also observed in zebrafish with knockouts of both paralogues the obligatory GluN1 subunit of the NMDAR. 82 Thus, while it is clear that neurosteroids with modulatory action at GABARs and NMDARs can profoundly influence CNS function, further research is needed to better understand how individual steroids and their metabolites act in concert to alter the balance of excitation and inhibition in neural circuits, with clinically relevant consequences for behavior.…”