Effects of Treadmill Training Combined with Serotonergic Interventions on Spasticity after Contusive Spinal Cord Injury

Spasticity usually emerges during the course of recovery from spinal cord injury (SCI). While medications and physical rehabilitation are prescribed to alleviate spastic symptoms, the insufficiency of their effects remains an important problem to be addressed. Given the challenges associated with increasing the dose of medication, we hypothesized that a combination therapy with medication and physical rehabilitation can be effective. Therefore, we examined the effects of treadmill training (TMT) along with serotonergic medication using a spastic rat model after contusive injury. Spasticity-strong SCI rats were selected 4 weeks after SCI and received one of the following interventions for 2 weeks: only TMT, TMT with fluoxetine (a selective serotonin re-uptake inhibitor), TMT with cyproheptadine (a 5-HT2 receptor antagonist), only fluoxetine, or only cyproheptadine. We performed the swimming test to quantify the frequency of spastic behaviors. We also evaluated hindlimb locomotor functions every week. At the end of the intervention, we examined the Hoffman reflex from the plantar muscle and the immunoreactivity of the 5-HT2A receptor in spinal cord tissues. While the TMT group and cyproheptadine-treated groups showed decreased spastic behaviors and reduction in spinal hyperreflexia, the fluoxetine-treated group showed the opposite effect, even with TMT. Moreover, TMT suppressed the expression of the 5-HT2A receptor in the lumbar spinal motor neurons, while cyproheptadine treatment did not change it. We did not observe any differences in locomotor functions between the groups. Taken together, our findings indicate that TMT and cyproheptadine significantly alleviated spastic symptoms, but did not show synergistic or additive effects.