BACKGROUND: Evaluation of the effects of candidate drugs on the nervous system in preclinical safety pharmacology studies utilises a global neurobehavioral assessment, usually in the rat. This either takes the form of the functional observational battery (FOB) or modified Irwin Test, both of which evaluate effects across 4 functional domains: autonomic, neuromuscular, sensorimotor and behavioral. Although there is a great deal of overlap in the parameters they address, the two tests approach the assessments slightly differently. We undertook a broad pharmacological validation of both the FOB and the Irwin test, and compared the two outcomes. METHODS: Male rats (6 per treatment group) were used to assess each of 12 reference drugs alongside vehicle controls in separate FOB and Irwin studies. The drugs compared in the two study types were chlorpromazine, chlordiazepoxide, clonidine, baclofen, (+)-amphetamine, harmaline, 8-hydroxy-2-(di-n-propylamino)tetralin, buspirone, physostigmine, picrotoxin, yohimbine and atropine. There is a high degree of semantic equivalence in the parameters assessed in the autonomic domain between the two tests, with a lower degree of equivalence for neuromuscular and behavioral domains, whereas sensorimotor reflex testing in the FOB is far more extensive than in the Irwin test. RESULTS: Across the set of reference drugs, concordance between the two tests was generally good across the 4 functional domains at the 'domain' level (i.e., detecting 'an effect'), whereas there was generally a poor concordance at the individual parameter level. However, this was partially explained by variability between repeated studies on a single reference drug using the same test (FOB or Irwin). CONCLUSIONS: Both tests are 'fit-for-purpose' in detecting effects of candidate drugs on the nervous system. We would encourage the global safety pharmacology community to consider whether (a) the tests could be combined into one industry standard; (b) candidate drugs could be triaged according to CNS penetration, with the level of scrutiny in the CNS core battery assessment adjusted accordingly and (c) whether new home cage technology could be applied to semi-automate the preclinical neurobehavioral assessment.
BACKGROUND: Evaluation of the effects of candidate drugs on the nervous system in preclinical safety pharmacology studies utilises a global neurobehavioral assessment, usually in the rat. This either takes the form of the functional observational battery (FOB) or modified Irwin Test, both of which evaluate effects across 4 functional domains: autonomic, neuromuscular, sensorimotor and behavioral. Although there is a great deal of overlap in the parameters they address, the two tests approach the assessments slightly differently. We undertook a broad pharmacological validation of both the FOB and the Irwin test, and compared the two outcomes. METHODS: Male rats (6 per treatment group) were used to assess each of 12 reference drugs alongside vehicle controls in separate FOB and Irwin studies. The drugs compared in the two study types were chlorpromazine, chlordiazepoxide, clonidine, baclofen, (+)-amphetamine, harmaline, 8-hydroxy-2-(di-n-propylamino)tetralin, buspirone, physostigmine, picrotoxin, yohimbine and atropine. There is a high degree of semantic equivalence in the parameters assessed in the autonomic domain between the two tests, with a lower degree of equivalence for neuromuscular and behavioral domains, whereas sensorimotor reflex testing in the FOB is far more extensive than in the Irwin test. RESULTS: Across the set of reference drugs, concordance between the two tests was generally good across the 4 functional domains at the 'domain' level (i.e., detecting 'an effect'), whereas there was generally a poor concordance at the individual parameter level. However, this was partially explained by variability between repeated studies on a single reference drug using the same test (FOB or Irwin). CONCLUSIONS: Both tests are 'fit-for-purpose' in detecting effects of candidate drugs on the nervous system. We would encourage the global safety pharmacology community to consider whether (a) the tests could be combined into one industry standard; (b) candidate drugs could be triaged according to CNS penetration, with the level of scrutiny in the CNS core battery assessment adjusted accordingly and (c) whether new home cage technology could be applied to semi-automate the preclinical neurobehavioral assessment.
Authors: Jean G Sathish; Siddhartha Bhatt; Jamie K DaSilva; Declan Flynn; Stephen Jenkinson; Amit S Kalgutkar; Maggie Liu; Balasubramanian Manickam; Jason Pinkstaff; William J Reagan; Norimitsu Shirai; Ahmed M Shoieb; Madhu Sirivelu; Saurabh Vispute; Allison Vitsky; Karen Walters; Todd A Wisialowski; Lawrence W Updyke Journal: Int J Toxicol Date: 2022-05-21 Impact factor: 2.380
Authors: Sergio A Zaizar-Fregoso; Brenda A Paz-Michel; Alejandrina Rodriguez-Hernandez; Juan Paz-Garcia; Nomely S Aurelien-Cabezas; Daniel Tiburcio-Jimenez; Valery Melnikov; Efren Murillo-Zamora; Osiris G Delgado-Enciso; Ariana Cabrera-Licona; José Guzman-Esquivel; Carlos E Barajas-Saucedo; Iram P Rodriguez-Sanchez; Margarita L Martinez-Fierro; Norma A Moy-López; Agustin Lara-Esqueda; Jorge Guzman-Muñiz; Marina Delgado-Machuca; Ivan Delgado-Enciso Journal: Evid Based Complement Alternat Med Date: 2022-06-02 Impact factor: 2.650