Contribution of 5-HT2 Receptors to the Control of the Spinal Locomotor System in Intact Rats.

Henryk Majczyński,Larry M Jordan,Urszula Sławińska,Anna M Cabaj

doi:10.3389/fncir.2020.00014

Abstract

Applying serotonergic (5-HT) agonists or grafting of fetal serotonergic cells into the spinal cord improves locomotion after spinal cord injury. Little is known about the role of 5-HT receptors in the control of voluntary locomotion, so we administered inverse agonists of 5-HT2 (Cyproheptadine; Cypr), 5-HT2A neutral antagonist (Volinanserin; Volin), 5-HT2C neutral antagonist (SB 242084), and 5-HT2B/2C inverse agonist (SB 206553) receptors intrathecally in intact rats and monitored their effects on unrestrained locomotion. An intrathecal cannula was introduced at the low thoracic level and pushed caudally until the tip reached the L2/L3 or L5/L6 spinal segments. Locomotor performance was evaluated using EMG activity of hindlimb muscles during locomotion on a 2 m long runway. Motoneuron excitability was estimated using EMG recordings during dorsi- and plantar flexion at the ankle. Locomotion was dramatically impaired after the blockage of 5-HT2A receptors. The effect of Cypr was more pronounced than that of Volin since in the L5/L6 rats Cypr (but not Volin) induced significant alteration of the strength of interlimb coordination followed by total paralysis. These agents significantly decreased locomotor EMG amplitude and abolished or substantially decreased stretch reflexes. Blocking 5-HT2B/2C receptors had no effect either on locomotion or reflexes. We suggest that in intact rats serotonin controls timing and amplitude of muscle activity by acting on 5-HT2A receptors on both CPG interneurons and motoneurons, while 5-HT2B/2C receptors are not involved in control of the locomotor pattern in lumbar spinal cord.

Highlights

There is recent evidence that the appearance of locomotor activity after spinal cord injury is due to 5-HT2C receptors that became constitutively active after injury (Fouad et al, 2010; Murray et al, 2010). 5-HT receptors that predominate in the control of locomotion in uninjured animals has not been established, nor has any role for 5-HT2C receptors in normal locomotion investigated
We hypothesized that intrathecal application of antagonists or inverse agonists to the 5-HT receptors implicated in locomotor control in intact rats can provide new insights into the receptors that predominate in voluntary control of locomotion
This was accompanied by rhythmic EMG activity in hindlimb muscles (Figures 2F,H), the EMG amplitude was smaller than before drug application (Figures 2B,D). After this stage of impairment, which lasted 10–20 min, the body weight support (BWS) gradually returned to the pre-drug level and animals started to use their hindlimbs to perform regular four-limb locomotion

Summary

Introduction

There is recent evidence that the appearance of locomotor activity after spinal cord injury is due to 5-HT2C receptors that became constitutively active after injury (Fouad et al, 2010; Murray et al, 2010). 5-HT receptors that predominate in the control of locomotion in uninjured animals has not been established, nor has any role for 5-HT2C receptors in normal locomotion investigated. 5-HT receptors that predominate in the control of locomotion in uninjured animals has not been established, nor has any role for 5-HT2C receptors in normal locomotion investigated. Pharmacological evidence using agonists has demonstrated contributions of several 5-HT receptors to the initiation and control of locomotion in the isolated spinal cord of neonatal animals, but few studies have tested the contributions of these receptors to the ability of 5-HT to control locomotion in adult, intact animals. A 5-HT2A/5-HT2C (but not 5-HT2B) agonist, is a potent stimulant of locomotor activity in animals (cats, rats and mice) with spinal cord injury (Barbeau and Rossignol, 1990, 1991; Antri et al, 2002, 2003; Gerasimenko et al, 2007; Courtine et al, 2009; Musienko et al, 2011; Ghosh and Pearse, 2014; Sławinska et al, 2014a). We investigated the role of these receptors in intact adult rats

Methods

Results

Conclusion