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 necrosis factor-α and interleukin-6 in the 
forelimb flexors. Interleukin-6 mRNA expression was remarkably reduced in the 
amygdala of mdx mice by chronic amitriptyline treatment. Positive effects of 
amitriptyline on mood, in addition to its anti-inflammatory effects in skeletal 
muscle, may make it an attractive therapeutic option for individuals with DMD.