Experimental Physiology 1370 Exp Physiol 99.10 (2014) pp 1370–1386 Research Paper Research Paper Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy Jennifer Manning 1,2 , Rebecca Kulbida 2 , Prerana Rai 3,4 , Lindsay Jensen 4 , Judith Bouma 3 , Sanjay P. Singh 4 , Dervla O’Malley 1 and Deniz Yilmazer-Hanke 2,3 1 Department of Physiology, University College Cork, Cork, Ireland 2 Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland 3 Department of Biomedical Sciences, Creighton University, School of Medicine, Omaha, NE, USA 4 Department of Neurology, Creighton University, School of Medicine, Omaha, NE, USA New Findings  What is the central question of this study? Individuals suffering from Duchenne muscular dystrophy show progressive deterioration of muscle function associated with muscle inflammation and are susceptible to anxiety and depression. The central question in this study is whether the tricyclic antidepressant amitriptyline can alleviate symptoms of anxiety and depression, and at the same time has anti-inflammatory effects in mdx mice, which are a model of Duchenne muscular dystrophy.  What is the main finding and its importance? Amitriptyline reduced inflammation and cytokines in mdx skeletal muscle, and had anxiolytic and antidepressant effects in mdx mice. Moreover, amitriptyline elevated the level of serotonin but reduced the expression of the cytokine interleukin-6 in the amygdala of mdx mice. Mutations in the structural protein dystrophin underlie muscular dystrophies characterized by progressive deterioration of muscle function. Dystrophin-deficient mdx mice are considered a model for Duchenne muscular dystrophy (DMD). Individuals with DMD are also susceptible to mood disorders, such as depression and anxiety. Therefore, the study objectives were to investigate the effects of the tricyclic antidepressant amitriptyline on mood, learning, central cytokine expression and skeletal muscle inflammation in mdx mice. Amitriptyline-induced effects (10 mg kg -1 daily s.c. injections, 25 days) on the behaviour of mdx mice were investigated using the open field arena and tail suspension tests. The effects of chronic amitriptyline treatment on inflammatory markers were studied in the muscle and plasma of mdx mice, and mood-associated monoamine and cytokine concentrations were measured in the amygdala, hippocampus, prefrontal cortex, striatum, hypothalamus and midbrain. The mdx mice exhibited increased levels of anxiety and depressive-like behaviour compared with wild-type mice. Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus. Inflammation in mdx skeletal muscle tissue was also reduced following amitriptyline treatment as indicated by decreased immune cell infiltration of muscle and lower levels of the pro-inflammatory cytokines tumour DOI: 10.1113/expphysiol.2014.079475 C  2014 The Authors. Experimental Physiology C  2014 The Physiological Society