Serotonergic Facilitation of Forelimb Functional Recovery in Rats with Cervical Spinal Cord Injury

Abstract

Serotonergic agents can improve the recovery of motor ability after a spinal cord injury. Herein, we compare the effects of buspirone, a 5-HT 1A receptor partial agonist, to fluoxetine, a selective serotonin reuptake inhibitor, on forelimb motor function recovery after a C4 bilateral dorsal funiculi crush in adult female rats. After injury, single pellet reaching performance and forelimb muscle activity decreased in all rats. From 1 to 6 weeks after injury, rats were tested on these tasks with and without buspirone (1-2 mg/kg) or fluoxetine (1-5 mg/kg). Reaching and grasping success rates of buspirone-treated rats improved rapidly within 2 weeks after injury and plateaued over the next 4 weeks of testing. Electromyography (EMG) from selected muscles in the dominant forelimb showed that buspirone-treated animals used new reaching strategies to achieve success after the injury. However, forelimb performance dramatically decreased within 2 weeks of buspirone withdrawal. In contrast, fluoxetine treatment resulted in a more progressive rate of improvement in forelimb performance over 8 weeks after injury. Neither buspirone nor fluoxetine significantly improved quadrupedal locomotion on the horizontal ladder test. The improved accuracy of reaching and grasping, patterns of muscle activity, and increased excitability of spinal motor-evoked potentials after buspirone administration reflect extensive reorganization of connectivity within and between supraspinal and spinal sensory-motor netxcopy works. Thus, both serotonergic drugs, buspirone and fluoxetine, neuromodulated these networks to physiological states that enabled markedly improved forelimb function after cervical spinal cord injury.

Buspirone Dose-Response on Facilitating Forelimb Functional Recovery in Cervical Spinal Cord Injured Rats

“…28 In a previous study, we showed that an incremental dose of Buspirone (1 to 2 mg/kg) can improve forelimb reaching function in rats with cervical cord injury. 29 The spontaneous recovery of forelimb function of rats without any drug intervention was found to be less than 20% while the rats which were administered Buspirone reached a success rate of over 60% by 6 weeks post-injury. Thus, serotonergic modulation enabled over 3-fold improvements in forelimb reaching and grasping after post-injury Buspirone administration.…”

Serotonergic Modulation of Spinal Circuitry Restores Motor Function after Chronic Spinal Cord Injury

“…Serotonergic agonists have been used extensively to promote motor recovery after SCI (35)(36)(37)(38)(39)(40)(41)(42)(43). However, only transient benefits were observed in these studies.…”

“…While the longevity of motor gains is remarkable, serotonergic therapy was initiated the day after SCI. Furthermore, serotonergic interventions were delivered during the acute or subacute phase of the injury in all the above studies (35)(36)(37)(38)(39)(40)(41)(42)(43)79). However, the majority of SCI patients have chronic injuries.…”

“…Previous studies have shown that serotonergic therapies can promote motor gains after SCI (35)(36)(37)(38)(39)(40)(41)(42)(43). Serotonin-receptor agonists were able to induce stepping and rhythmogenesis in spinalized rats after thoracic injuries through activation of spinal locomotor networks (35)(36)(37)(38)(39)(40)43).…”

“…While serotonergic agonists have been extensively examined after thoracic SCI (35-40, 43), administration of 5-hydroxytryptophan, which is a 5-HT precursor, also evoked activity in phrenic motoneurons following a C1 – C2 transection (41). Additionally, delivery of serotonergic agonists produced recovery of skilled reach and grasp movements after a C4 injury (42). However, therapeutic benefits did not persist after withdrawal of the neuromodulators in these studies.…”