Spasticity is a common and disabling symptom observed in patients with central 
nervous system diseases, including amyotrophic lateral sclerosis, a disease 
affecting both upper and lower motor neurons. In amyotrophic lateral sclerosis, 
spasticity is traditionally thought to be the result of degeneration of the 
upper motor neurons in the cerebral cortex, although degeneration of other 
neuronal types, in particular serotonergic neurons, might also represent a cause 
of spasticity. We performed a pathology study in seven patients with amyotrophic 
lateral sclerosis and six control subjects and observed that central 
serotonergic neurons suffer from a degenerative process with prominent neuritic 
degeneration, and sometimes loss of cell bodies in patients with amyotrophic 
lateral sclerosis. Moreover, distal serotonergic projections to spinal cord 
motor neurons and hippocampus systematically degenerated in patients with 
amyotrophic lateral sclerosis. In SOD1 (G86R) mice, a transgenic model of 
amyotrophic lateral sclerosis, serotonin levels were decreased in brainstem and 
spinal cord before onset of motor symptoms. Furthermore, there was noticeable 
atrophy of serotonin neuronal cell bodies along with neuritic degeneration at 
disease onset. We hypothesized that degeneration of serotonergic neurons could 
underlie spasticity in amyotrophic lateral sclerosis and investigated this 
hypothesis in vivo using tail muscle spastic-like contractions in response to 
mechanical stimulation as a measure of spasticity. In SOD1 (G86R) mice, tail 
muscle spastic-like contractions were observed at end-stage. Importantly, they 
were abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists. In line 
with this, 5-hydroxytryptamine-2b receptor expression was strongly increased at 
disease onset. In all, we show that serotonergic neurons degenerate during 
amyotrophic lateral sclerosis, and that this might underlie spasticity in mice. 
Further research is needed to determine whether inverse agonists of 
5-hydroxytryptamine-2b/c receptors could be of interest in treating spasticity 
in patients with amyotrophic lateral sclerosis.