Contribution of spinal 5-HT1A and 5-HT7 receptors to locomotor-like movement induced by 8-OH-DPAT in spinal cord-transected mice

Growing evidence from in vitro studies suggests that spinal serotonin (5-HT) receptor subtypes 5-HTR1A and 5-HTR7 are associated with an induction of central pattern generator activity. However, the possibility of a specific role for these receptor subtypes in locomotor rhythmogenesis in vivo remains unclear. Here, we studied the effects of a single dose (1 mg/kg, i.p.) of 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT), a potent and selective 5-HTR1A/7 agonist, in mice spinal cord transected at the low-thoracic level (Th9/10). The results show that 8-OH-DPAT acutely induced, within 15 min, hindlimb movements that share some characteristics with normal locomotion. Paraplegic mice pretreated with the selective 5-HTR1A antagonists, WAY100,135 or WAY100,635, displayed significantly less 8-OH-DPAT-induced movement. A similar reduction of 8-OH-DPAT-induced movements was found in animals pretreated with SB269970, a selective 5-HTR7 antagonist. Moreover, a near complete blockade of 8-OH-DPAT-induced movement was obtained in wild-type mice pretreated with 5-HTR1A and 5-HTR7 antagonists, and in 5-HTR7-/- mice pretreated with 5-HTR1A antagonists. Overall, these results clearly demonstrate that 8-OH-DPAT potently induces locomotor-like movement in the previously paralysed hindlimbs of low-thoracic-transected mice. The results, with selective antagonists and knockout animals, provide compelling evidence of a specific contribution of both receptor subtypes to spinal locomotor rhythmogenesis in vivo.