Role of spinal 5-HT2 receptor subtypes in quipazine-induced hindlimb movements after a low-thoracic spinal cord transection

A role of serotonin receptors (5-HTRs) in spinal rhythmogenesis has been proposed several years ago based mainly upon data showing that bath-applied 5-HT could elicit locomotor-like rhythms in in vitro isolated spinal cord preparations. Such a role was partially confirmed in vivo after revealing that systemically administered 5-HTR2 agonists, such as quipazine, could induce some locomotor-like movements (LM) in completely spinal cord-transected (Tx) rodents. However, given the limited binding selectivity of currently available 5-HTR2 agonists, it has remained difficult to determine clearly if one receptor subtype is specifically associated with LM induction. In situ hybridization, data using tissues from L1-L2 spinal cord segments, where critical locomotor network elements have been identified in mice, revealed greater 5-HTR2A mRNA levels in low-thoracic Tx than non-Tx animals. This expression level remained elevated for several days, specifically in the lateral intermediate zone, where peak values were detected at 1 week post-Tx and returned to normal at 3 weeks post-Tx. Behavioral and kinematic analyses revealed quipazine-induced LM in 1-week Tx mice either non-pretreated or pretreated with selective 5-HTR2B and/or 5-HTR2C antagonists. In contrast, LM completely failed to be induced by quipazine in animals pretreated with selective 5-HTR2A antagonists. Altogether, these results provide strong evidence suggesting that 5-HTR2A are specifically associated with spinal locomotor network activation and LM generation induced by quipazine in Tx animals. These findings may contribute to design drug treatments aimed at promoting locomotor function recovery in chronic spinal cord-injured patients.