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Methods to Quantify Pharmacologically Induced Alterations in Motor Function in Human Incomplete SCI
Published on: April 18, 2011
Differential effects of 5-HT1 and 5-HT2 receptor agonists on hindlimb movements in paraplegic mice
Eric S Landry1, Pierre A Guertin
1Department of Anatomy and Physiology, Laval University, Research Centre of the Laval University Research Hospital (CRCHUL-CHUQ), 2705 Bld Laurier, RC-9800, Quebec City, Quebec, G1V4G2, Canada.
Abstract:
The effects induced by serotonergic (5-HT) agonists of the 5-HT1 and 5-HT2 subclasses were examined on hindlimb movement generation in adult mice completely spinal cord transected at the low thoracic level. One week postspinalization, intraperitoneal injection (0.5-10 mg/kg) of meta-chlorophenylpiperazine (m-CPP; 5-HT(2B/2C) agonist) or trifluoromethylpiperazine (TFMPP; 5-HT(1B) agonist) failed to induce locomotor-like movements. However, dose-dependent nonlocomotor movements were induced in air-stepping condition or on a motor-driven treadmill. In contrast, hindlimb locomotor-like movements were found after the injection of quipazine (5-HT(2A/2C) agonist; 1-2 mg/kg). Combined with L-DOPA (50 mg/kg, i.p.), low doses of quipazine but not of m-CPP and TFMPP produced locomotor-like and nonlocomotor movements in air-stepping condition or on the treadmill. Subsequent administration of m-CPP or TFMPP significantly reduced and often completely abolished the hindlimb movements induced by quipazine and L-DOPA. Altogether, these results demonstrate that 5-HT(2A/2C) receptor agonists promote locomotion while 5-HT(1B) and 5-HT(2B/2C) receptor agonists interfere with locomotor genesis in the hindlimbs of complete paraplegic mice. These results suggest that only subsets of spinal 5-HT receptors are specific to locomotor rhythmogenesis and should be activated to successfully induce stepping movements after spinal cord injury.
Insights
Serotonin receptor 5-HT(2A/2C) agonists promote hindlimb locomotion in spinal cord injury mice, while other serotonin receptor subtypes interfere. Activating specific spinal 5-HT receptors is key for inducing stepping movements post-injury.
Area of Science:
- Neuroscience
- Spinal Cord Injury Research
- Pharmacology
Background:
- Spinal cord injury (SCI) often results in paraplegia, impairing hindlimb movement.
- Serotonergic (5-HT) pathways play a crucial role in motor control and locomotion.
- Understanding the specific roles of different 5-HT receptor subtypes is vital for developing therapeutic strategies for SCI.
Purpose of the Study:
- To investigate the effects of specific serotonergic agonists on hindlimb movement generation in adult mice with complete spinal cord transection.
- To determine which 5-HT receptor subclasses are involved in promoting or inhibiting locomotor activity after SCI.
Main Methods:
- Adult mice underwent low thoracic spinal cord transection.
- One week post-spinalization, various 5-HT agonists (m-CPP, TFMPP, quipazine) were administered intraperitoneally.
- Locomotor and nonlocomotor movements were assessed in air-stepping and on a treadmill, with and without L-DOPA co-administration.
Main Results:
- 5-HT(2A/2C) agonist (quipazine) induced hindlimb locomotor-like movements.
- 5-HT(1B) (TFMPP) and 5-HT(2B/2C) (m-CPP) agonists induced nonlocomotor movements but did not promote locomotion.
- Co-administration with L-DOPA enhanced quipazine's effects, while m-CPP and TFMPP inhibited quipazine- and L-DOPA-induced movements.
Conclusions:
- 5-HT(2A/2C) receptor activation promotes locomotion, whereas 5-HT(1B) and 5-HT(2B/2C) receptor activation interferes with hindlimb movement generation in paraplegic mice.
- Specific subsets of spinal 5-HT receptors are critical for locomotor rhythmogenesis and should be targeted for therapeutic interventions after SCI.
