Christina Möller1, Fabio Wolf1, R Maarten van Dijk1, Valentina Di Liberto1, Vera Russmann1, Michael Keck1, Rupert Palme2, Rainer Hellweg3, Peter Gass4, Christiane Otzdorff5, Heidrun Potschka1. 1. Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany. 2. Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria. 3. Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany. 4. Central Institute of Mental Health Mannheim (ZI), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany. 5. Clinic of Small Animal Surgery and Reproduction, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University, Munich, Germany.
Abstract
OBJECTIVE: Rodent epilepsy models can significantly contribute to our understanding of pathophysiological mechanisms and to validation of biomarker and target candidates. Evidence-based severity assessment is a presupposition for the ethical evaluation of animal experimentation allowances as well as for the development of efficacious refinement concepts. METHODS: Aiming to improve our understanding of the impact of experimental procedures and repeated seizures, we have completed a comprehensive behavioral and biochemical analysis assessing various parameters that can inform about the influence of an electrical kindling paradigm on well-being in rats. Thereby, we have focused on the immediate effects of phases with focal and generalized seizures with behavioral testing during kindling acquisition. RESULTS: Electrode implantation exerted mild effects on anxiety-associated behavior and reduced serum corticosterone at 3 weeks, but not 7 weeks, following surgery. Analysis in kindled rats excluded any relevant impact of focal seizures on behavioral and biochemical parameters. Assessment in rats with generalized seizures revealed an impact on nest complexity scores, nest soiling, and selected parameters in paradigms evaluating anxiety-associated behavior. Moreover, serum corticosterone levels, but neither hair corticosterone nor fecal corticosterone metabolite concentrations were lowered as a consequence of repeated generalized seizures. The assessment of various other behavioral and biochemical parameters did not reveal any other relevant effects of generalized seizures. Cross-correlation analysis suggested that assessment of nest building and maintenance can provide information comparable to that from more elaborate behavioral assays. This finding provides first evidence that nest scoring might serve as a simple and valid approach to evaluate rat well-being during routine assessment schemes. SIGNIFICANCE: The findings argue against a persistent level of pronounced distress and suggest a classification of the kindling paradigm as a model with moderate severity based on a longer-lasting mild impact on animal behavioral patterns. This suggestion provides a basis for a prospective and retrospective case-by-case severity assessment.
OBJECTIVE: Rodent epilepsy models can significantly contribute to our understanding of pathophysiological mechanisms and to validation of biomarker and target candidates. Evidence-based severity assessment is a presupposition for the ethical evaluation of animal experimentation allowances as well as for the development of efficacious refinement concepts. METHODS: Aiming to improve our understanding of the impact of experimental procedures and repeated seizures, we have completed a comprehensive behavioral and biochemical analysis assessing various parameters that can inform about the influence of an electrical kindling paradigm on well-being in rats. Thereby, we have focused on the immediate effects of phases with focal and generalized seizures with behavioral testing during kindling acquisition. RESULTS: Electrode implantation exerted mild effects on anxiety-associated behavior and reduced serum corticosterone at 3 weeks, but not 7 weeks, following surgery. Analysis in kindled rats excluded any relevant impact of focal seizures on behavioral and biochemical parameters. Assessment in rats with generalized seizures revealed an impact on nest complexity scores, nest soiling, and selected parameters in paradigms evaluating anxiety-associated behavior. Moreover, serum corticosterone levels, but neither hair corticosterone nor fecal corticosterone metabolite concentrations were lowered as a consequence of repeated generalized seizures. The assessment of various other behavioral and biochemical parameters did not reveal any other relevant effects of generalized seizures. Cross-correlation analysis suggested that assessment of nest building and maintenance can provide information comparable to that from more elaborate behavioral assays. This finding provides first evidence that nest scoring might serve as a simple and valid approach to evaluate rat well-being during routine assessment schemes. SIGNIFICANCE: The findings argue against a persistent level of pronounced distress and suggest a classification of the kindling paradigm as a model with moderate severity based on a longer-lasting mild impact on animal behavioral patterns. This suggestion provides a basis for a prospective and retrospective case-by-case severity assessment.
Authors: Roelof Maarten van Dijk; Ines Koska; Andre Bleich; Rene Tolba; Isabel Seiffert; Christina Möller; Valentina Di Liberto; Steven Roger Talbot; Heidrun Potschka Journal: PLoS One Date: 2020-05-15 Impact factor: 3.240