Spinal Cord-Transected Mice Learn to Step in Response to Quipazine Treatment and Robotic Training

Abstract

In the present study, concurrent treatment with robotic step training and a serotonin agonist, quipazine, generated significant recovery of locomotor function in complete spinal cord-transected mice (T7-T9) that otherwise could not step. The extent of recovery achieved when these treatments were combined exceeded that obtained when either treatment was applied independently. We quantitatively analyzed the stepping characteristics of spinal mice after alternatively administering no training, manual training, robotic training, quipazine treatment, or a combination of robotic training with quipazine treatment, to examine the mechanisms by which training and quipazine treatment promote functional recovery. Using fast Fourier transform and principal components analysis, significant improvements in the step rhythm, step shape consistency, and number of weight-bearing steps were observed in robotically trained compared with manually trained or nontrained mice. In contrast, manual training had no effect on stepping performance, yielding no improvement compared with nontrained mice. Daily bolus quipazine treatment acutely improved the step shape consistency and number of steps executed by both robotically trained and nontrained mice, but these improvements did not persist after quipazine was withdrawn. At the dosage used (0.5 mg/kg body weight), quipazine appeared to facilitate, rather than directly generate, stepping, by enabling the spinal cord neural circuitry to process specific patterns of sensory information associated with weight-bearing stepping. Via this mechanism, quipazine treatment enhanced kinematically appropriate robotic training. When administered intermittently during an extended period of robotic training, quipazine revealed training-induced stepping improvements that were masked in the absence of the pharmacological treatment.

Increased Lower Limb Spasticity but Not Strength or Function Following a Single-Dose Serotonin Reuptake Inhibitor in Chronic Stroke

“…Regardless, the present data are consistent with selected studies in animal models 52 and humans of neurologic injury (SCI) 51 indicating no immediate improvements in locomotion function with single-dose enhancement of 5-HT transmission. These findings are of clinical interest because previous data suggest improvements in motor function after prolonged SSRI use, although greater changes were observed in upper versus lower limbs.…”

Training locomotor networks

“…Relatively modest dosages of the serotonergic agonist, quipazine, have a similar effect. Although higher doses of quipazine and other excitatory drugs can induce locomotor-like movements, quipazine in itself does not induce and control stepping at lesser dosages (Fong et al, 2005;Guertin et al, 2004) Thus, it can modulate the inhibitory and excitatory properties of spinal neural circuits to a net excitable state that step-related proprioception can generate successful movements.…”

“…Fewer studies have examined the role of these pharmacological manipulations on the locomotor output under in vivo conditions. There are reasonably clear examples that administration of α-2 adrenergic agonists (e.g., clonidine) (Giroux et al, 1998), serotonergic agonists (e.g., quipazine) (Barbeau and Rossignol, 1990;Fong et al, 2005), glycinergic agonists (e.g., strychnine) de Leon et al, 1999, and GABAergic agonists (e.g., Robinson and Goldberger, 1986) can improve the locomotion of complete spinal animals, particularly when the locomotor capability is very poor prior to the pharmacological treatment. In most of these studies, however, a distinction is not made as to whether the pharmacological agent is actually inducing locomotion vs. changing the physiological state of the spinal cord so that it can generate locomotion when the afferent systems are allowed to control the motor output.…”

“…In most of these studies, however, a distinction is not made as to whether the pharmacological agent is actually inducing locomotion vs. changing the physiological state of the spinal cord so that it can generate locomotion when the afferent systems are allowed to control the motor output. In reports of the facilitation of locomotion in response to either strychnine or quipazine, it was clear that the drug itself, at least for the dosages used, did not induce stepping (Cai et al, 2006b;de Leon et al, 1999;Fong et al, 2005). When the hindlimbs were placed on a moving treadmill belt after administration of the drug, however, effective weight-bearing locomotion could be generated.…”

“…To address the question of whether there was an important interactive effect of the pharmacological intervention and the training, we administered the 5-HT receptor agonist quipazine daily to a group of spinal mice that were step trained and to a group that were not trained (Cai et al, 2006b;Fong et al, 2005). The non-trained mice receiving quipazine showed no sustained improvement in stepping over a period of several weeks, whereas the trained mice receiving quipazine showed a significant improvement in stepping ability.…”