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

Abstract

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-HTR(2) 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-HTR(2) 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-HTR(2A) 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-HTR(2B) and/or 5-HTR(2C) antagonists. In contrast, LM completely failed to be induced by quipazine in animals pretreated with selective 5-HTR(2A) antagonists. Altogether, these results provide strong evidence suggesting that 5-HTR(2A) 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.

Effects of antidepressant and treadmill gait training on recovery from spinal cord injury in rats

“…9 This increased number of receptors appears to have potential for treatment, because serotonin receptor agonists have been shown to improve motor deficits. 6,7 Serotonin precursors have also exhibited positive effects on motor recovery. 9 Experimental studies have sought to elucidate potential synergism among different pharmacological treatments for SCI.…”

“…Moreover, serotonin reuptake inhibitors appear to have a positive effect on limb movement in individuals with SCIs. [6][7][8] The loss of regulatory descending serotonergic mechanisms after SCI contributes to motor deficits and causes increased numbers of serotonin receptors in spinal cord segments below the injury. 9 This increased number of receptors appears to have potential for treatment, because serotonin receptor agonists have been shown to improve motor deficits.…”

Modulation of Intrinsic Spiking in Spinal Cord Neurons

“…The 5-HT 2 receptor agonist quipazine enhances locomotor function in rats that received neural transplants after spinal transsection (Kim et al 1999) and promotes recovery of hindlimb movement after spinal cord injury (Antri et al 2005;Ung et al 2008). Our finding of an activation of silent neurons with 5-HT through 5-HT 2 receptors may help to explain how quipazine can promote rhythms and functional recovery of locomotion.…”

“…In the neocortex, I NaP is found in a subtype of persistently active neurons in layers 2/3 and 5 (Aracri et al 2006). In these cells, I NaP is necessary for the generation of "pacemaker-like activity" (Le Bon-Jego and Yuste 2007) and enables cortical neurons to generate network bursts (van Drongelen et al 2006). In the spinal cord, many studies show a contribution of I NaP to the enhancement of neuronal activity and the promotion of rhythm generation (Theiss et al 2007;Zhong et al 2007).…”

“…The activation of such a subthreshold depolarizing conductance is a crucial component in intrinsic spiking. I NaP is involved in rhythmic activity in the hippocampus (Jinno et al 2003), subthalamic neurons (Beurrier et al 2000), the neocortex (Van Drongelen et al 2006), pre-Bötzinger complex inspiratory neurons (Del Negro et al 2002), and spinal cord neurons (Darbon et al 2004;Tazerart et al 2007Tazerart et al , 2008Ziskind-Conhaim et al 2008). A previous study showed that I NaP is detected in intrinsically spiking cells in spinal cord cultures and underlies their rhythmic properties (Darbon et al 2004).…”