The role of serotonin on the modulation of locomotion and reflexes in mammals, primates and in humans with spinal cord injury

This review briefly reports the effects of serotonergic (5-HT) drugs on spinal reflexes as well as on the locomotor pattern in adult spinal animals of different species. In addition, this review also addresses the issue of serotonergic blockade on certain manifestations of spasticity at rest, during simple movement and during locomotion in human subjects with spinal cord injury (SCI). Several weeks or months following spinal transection in rats, injection of serotonergic drugs at rest markedly increased the spontaneous electromyographic (EMG) activity of the flexor and extensor muscles of the hindlimbs with torsion of the trunk, spasms and clonus. After transplant of embryonic 5-HT cells or i.p. injection of 5-HT agonists, rats can also express hindlimb locomotion on a treadmill. In spinal cats, 5-HT does not initiate locomotion in the early post-spinal period. However, when the cats can walk spontaneously, the 5-HT precursor 5-HTP or different agonists increased the EMG burst amplitude of the flexors, extensors and axial muscles resulting in an excellent weight support of the hindquarter. There is also an increase in general excitability so that spasms and clonus can interfere with locomotion. Moreover, serotonergic drugs increased the excitability of reflex responses in both the cutaneous and phasic stretch pathways. Cyproheptadine, a serotonergic antagonist, partially or completely blocked the effect of serotonergic agonist, decrease the EMG amplitude of lower limb and axial muscles during locomotion as well as on cutaneous and stretch reflexes, thus reducing the spastic features of complete spinal cats. In partial spinal cats, 5-HT agonists markedly improved the locomotor pattern. In SCI subjects, cyproheptadine, at a daily dose of 12 to 24 mg per day, markedly reduced such manifestations of spasticity (spasms, clonus). However, cyproheptadine also decreased the clonus during voluntary flexion of knee as well as during locomotion. During locomotion, cyproheptadine improved the coordination between the agonist and antagonist groups of muscles, which was associated with an improvement in joint angular displacement. Functionally, the SCI subjects gained the ability to walk at higher speeds on the treadmill and overground with walking aids. These results indicate that serotonergic drugs may modulate spinal locomotion and excitability of different spinal reflexes. They also suggest that cyproheptadine may have an important therapeutic role in SCI subjects by reducing manifestations of spasticity leading to the enhancement locomotor function. The possible implications of various mechanisms underlying these effects are discussed.