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Megarbane, B., Lesguillons, N., Galliot-Guilley, M., Borron, S.W., Trout, H., Decleves, X., Risede, P., Monier, C., Boschi, G. and Baud, F.J. (2005) Cerebral and plasma kinetics of a high dose of midazolam and correlations with its respiratory effects in rats. Toxicology Letters, 159, 22-31. doi:10.1016/j.toxlet.2005.04.003

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• TITLE: Purkinje-neuron-specific down-regulation of p38 protects motoric function from the repeated use of benzodiazepine

  AUTHORS: Marianna Jung, Daniel Metzger

  KEYWORDS: Benzodiazepine; Motoric Deficit; p38; Purkinje Neurons; Mitochondria

  JOURNAL NAME: Advances in Bioscience and Biotechnology, Vol.4 No.6A, June 20, 2013

  ABSTRACT: Benzodiazepine (BZD) is the most prescribed CNS depressant in America to treat hyper-excitatory disorders such as anxiety and insomnia. However, the chronic use of BZD often creates adverse effects including psychomotor deficit. In this study, we investigated a novel mechanism by which chronic BZD impedes motoric function in female mice. We used female mice because BZD use is much more prevalent in female than male populations. We tested the hypothesis that the accumulation of p38 (stress-activated protein) in cerebellar Purkinje neurons mediates motoric deficit induced by chronic BZD. To test this hypothesis, we generated transgenic mice that lack p38 incerebellar Purkinje neurons by crossing Pcp2 (Purkinje cell protein 2)-Cre mice with p38loxP/loxP mice. p38-knockdown mice and wild-type mice received BZD (lorazepam, 0.5 mg/kg) for 14 days. During this period, they were tested for motoric performance using Rotarod assay in which a quicker fall from rotating rod indicates poorer motoric performance. Cerebellum was then collected to detect p38 inPurkinje neurons and to measure mitochondrial respiration using immunohistochemistry and real-time XF respirometry, respectively. Compared to vehicletreated mice, BZD-treated mice showed poorer motoric performance, a higher number of Purkinje neurons containing p38, and lower mitochondrial respiration. These effects of BZD were much smaller in p38-knockdown mice. These results suggest that the excessive accumulation of p38 incerebellar Purkinje neurons contributes to motoric deficit associated with chronic BZD. They also suggest that Purkinje neuronal p38 mediates BZD-induced mitochondrial respiratory inhibition in cerebellum. Our findings may provide a new mechanistic insight into chronic BZD-induced motoric deficit.