A 5-HT locomotor system: Identification, actions through 5-HT(2A/7) receptor subtypes, and effects on the control of locomotion

Locomotion is controlled by neural networks in the spinal cord called central pattern generators (CPG). Accumulated evidence suggests that serotonin also known as 5-hydroxytryptamine (5-HT) is effective in the production of locomotor-like activity in neonatal in vitro spinal cord preparations of the rodent. It is well known that the serotonergic descending command system(s) play an important role in the control of locomotion. In this study, we first localized a discrete population of 5-HT cells in the parapyramidal region (PPR) of the medulla that when stimulated, evoked locomotor-like activity in the neonatal rat brainstem-spinal cord preparation. To identify 5-HT receptor subtypes responsible for PPR-evoked locomotion, various antagonists of 5-HT7 receptor subtypes were applied to the upper and lower lumbar segments of the spinal cord. We found that 5-HT7 receptors most likely affect neurons of CPG in the low thoracic and upper lumbar cord, whereas 5-HT2A receptors are more likely located more caudally involved in the output stage of the pattern generator for locomotion.; To further test the hypothesis that 5-HT7 receptors are critical for the production of locomotion in mammalians, we first performed experiments on both neonatal and adult mice with a targeted knockout of the 5-HT 7 receptor gene (5-HT7-/- mice). In the isolated spinal cord, locomotor-like activity induced by 5-HT in wild-type (5-HT 7+/+) mice was disrupted by the specific 5-HT7 receptor antagonist SB269970. In most cases, 5-HT evoked uncoordinated or synchronous rhythmic activity in 5-HT7-/- mice. Then, we tested the hypothesis that 5-HT7 receptors are involved in the control of voluntary locomotion in adult mice. Quantitative methods including kinematic measurements and electromyographic (EMG) recording were utilized in this study. Our data suggest that intrathecal administration of SB269970 at the levels of L1/2 consistently disrupted locomotion in 5-HT 7+/+ mice, producing "hyper-extension" of both hindlimbs or synchronous contraction of ipsilateral TA and GS muscle activity, resulting in slowed locomotion and "dragging" of the hindlimbs. 5-HT7 +/+ mice walk normally and in most 5-HT7-/- mice treated with SB-269970, no overt effects on locomotion were observed. These results strongly suggest that 5-HT7 receptors play an important role in the control of locomotion in adult as well as neonatal animals and parallel descending mechanisms contribute to activation of the CPG for locomotion.