Ionotropic 5-HT3 Receptor Agonist-Induced Motor Responses in the Hindlimbs of Paraplegic Mice

Department of Anatomy and Physiology, Laval University and Laval University Medical Center, Quebec City, Quebec, Canada Submitted 7 June 2005; accepted in final form 19 July 2005 Centrally expressed 5-HT 3 receptors (5-HTR 3 ) are well known for their role in wakefulness, cognition, and nociception. However, clear evidence of their participation in motor control is still lacking despite specific 5-HTR 3 expression in hindlimb motor areas of the spinal cord (i.e., lumbar laminae VII-IX). Here, we studied the acute effects of 4-amino-(6-chloro-2-pyridyl)-1-piperidine hydrochloride (SR 57227A), a potent and selective 5-HTR 3 agonist, on hindlimb movement generation in complete paraplegic mice. The induced movements were assessed in open-field, air-stepping, and treadmill conditions using a combination of qualitative and quantitative methods. The results revealed that SR 57227A (1–4 mg/kg ip) produced hindlimb movements corresponding to scores ranging from 1 to 5 on the motor scales of Basso, Beattie, and Bresnahan and of Antri, Orsal, and Barthe. Additional analyses revealed that one-third of the movements displayed on a treadmill were "locomotor-like" (i.e., bilateral alternation), whereas only nonlocomotor movements were observed in the other testing conditions suggesting a task-dependent contribution of peripheral afferent inputs to these effects. Locomotor-like movements could also be induced in open field and air stepping if SR 57227A was combined with subthreshold doses of 5-carboxytryptamine (5-HT 1A/7 receptor agonist), suggesting synergistic actions of these drugs on central neurons. These results demonstrate that 5-HTR 3 activation can induce motor activity and, under some conditions, rhythmic locomotor-like movements in the hindlimbs of paraplegic mice providing evidence of an unsuspected role for this receptor subtype in hindlimb motor control. Address for reprint requests and other correspondence: P. A. Guertin, CRCHUL, Neuroscience Unit, RC-9800, 2705 Laurier Bld., Quebec City, Quebec G1V 4G2, Canada (E-mail: pierre.guertin{at}crchul.ulaval.ca )