Spectrum of effects detected in the rat functional observational battery following administration of non-CNS targeted and CNS targeted compounds

Abstract

The Functional Observational Battery (FOB) is an established systematic evaluation of nervous system function in the rat, comprising more than 30 parameters across autonomic, neuromuscular, sensorimotor and behavioral domains. Assessment of CNS function using behavioral assays is largely dependent on multiple subjective endpoints, and the experience in test facility. To establish reference background data, and assess the sensitivity and specificity of the FOB test, we collected the FOB results from 360 studies performed in the past three years that were targeted for CNS and non-CNS disorders. Examination was performed with the technician blind to the animal's treatment. Approximately 11 % compounds tested had an effect in the FOB test, including 4 % CNS compounds, 3 % non-CNS indication compound, 1 % antidiabetic compounds, and 3 % others. These effects occurred with higher incidence at CNS indication compound were forelimb grip strength (1.9 %), hindlimb foot splay (1.9 %), low arousal (2.2 %), abnormal gait pattern (1.9 %), firm or flaccid body tone (2.2 %), firm or flaccid extensor response (1.7 %), uncoordinated landing in air righting reflex and abnormal palpebral closure (0.8 %). The most common effects noted for both CNS indication and non-CNS indication compound were changes in rectal temperature (7.8 % of studies), hindlimb grip strength (2.2 % of studies), locomotor activity (2.8 % of studies), rearing frequency (3.6 % of studies), abnormal posture (1.4 % of studies). Remaining FOB parameters were affected by 2 % CNS compounds and 2 % non-CNS indication compound. The parameters such as gait pattern, arousal, body tone, extensor response, forelimb grip strength and hindlimb foot splay are good indicators of CNS adverse events with higher incidence. The Functional Observational Battery (FOB) test is sensitivity for CNS targeted compounds, and can provide reference for potential pharmacological mechanisms and follow-up neurotoxicity studies. Individual parameters such as rearing frequency, locomotor activity, and hindlimb grip strength, rectal temperature had both high incidences in CNS and non-CNS incidences, and are not specific indicators of possible CNS adverse events. The FOB test as part of the safety pharmacology core battery is valuable for the assessment for non-CNS targeted compounds.