Refining drug screening with automated home cage monitoring: a crossover study in socially housed rats

Attrition in drug development due to central nervous system (CNS)-related adverse events is costly and can pose risks to volunteer safety during clinical development, underscoring the need to refine preclinical CNS screening strategies. The primary preclinical method to assess CNS risk is the Functional Observation Battery (FOB)/Irwin; however, these tests are limited by subjective assessment and restricted temporal resolution. Automated neurobehavioral assessment, such as the Home Cage Analyzer (HCA), may provide a solution to these challenges. Moreover, home cage assessments are in alignment with the 3Rs principles of refinement and reduction of animal use. Here, we detail our efforts to validate the HCA as part of GSK’s CNS safety assessment strategy. To this end, we evaluated the HCA using tool compounds-amphetamine, diazepam, and chlorpromazine-each with differing pharmacology and pharmacokinetics. Additionally, we employed a 4 × 4 Latin-square crossover study design allowing each animal to serve as its own control. Our results demonstrate that the HCA captured the expected pharmacological effects of stimulant and sedative compounds across differing light phases. Notably, at the highest amphetamine dose, we observed a distinct shift in behavior: horizontal locomotor activity decreased, vertical rearing activity markedly increased, a nuanced effect that could be missed by traditional observational methods and highlights the value of multimodal assessment. Together, these data strongly support the use of the HCA as a first-line tool in preclinical CNS safety assessment.