Validation of a Functional Observational Battery in the Minipig for Regulatory Neurotoxicity Assessments

Authors

Zhong, M., Fuller, A., Hanks, C., Brocksmith, D., Liu, J., Gad, S., Bouchard, G.F., Stricker-Krongrad, A.

Abstract

Background: A functional observational battery (FOB) is recommended as the first tier neurotoxicity screening in the preclinical safety pharmacology testing guidelines. The minipig has increasingly been used in regulatory toxicology studies; however, no current FOB protocol is available for the neurotoxicity testing in this species.

Purpose: To validate a minipig functional observational battery protocol.

Methods: A crossover study with Sinclair minipigs was performed to capture effects of amphetamine, ketamine and diazepam. The minipigs were observed in their home cage, were video-recorded for 10 minutes in a confined open field and went through a neurologic examination.

Results: Both ketamine and diazepam treated minipigs showed reduced interests in environmental changes and increased exploration interests, and had muscular malfunction and gaits impairment. On the other hand, unique and even opposite effects were also observed between ketamine and diazepam, which might reflect their unique mechanisms of action in treated minipigs. Effects of ketamine and diazepam were consistent with their roles in suppressing central nervous system (CNS) functions. Amphetamine is a CNS stimulant, which promotes dopamine-associated brain activities. Amphetamine treated minipigs were consistently shown to be hyperactive and to display increased interest to environmental changes and reduced exploring activities. Amphetamine also increased locomotion and induced biphasic behavior effects in the treated animals. The shared effects of ketamine and diazepam might result from their interference with dopamine functions in CNS, in contrast to those of amphetamine.

Conclusion: The Sinclair minipig is suitable for functional observational battery (FOB) evaluation of chemicals in preclinical safety pharmacology testing, and a reproducible quantitative approach is described.

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