5-HT₂ and 5-HT₇ receptor agonists facilitate plantar stepping in chronic spinal rats through actions on different populations of spinal neurons.

Urszula Så‚Awiå„Ska,Krzysztof Miazga,Larry M Jordan

doi:10.3389/fncir.2014.00095

Urszula Så‚Awiå„Ska, Krzysztof Miazga + Show 1 more

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https://doi.org/10.3389/fncir.2014.00095

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Abstract

There is considerable evidence from research in neonatal and adult rat and mouse preparations to warrant the conclusion that activation of 5-HT2 and 5-HT1A/7 receptors leads to activation of the spinal cord circuitry for locomotion. These receptors are involved in control of locomotor movements, but it is not clear how they are implicated in the responses to 5-HT agonists observed after spinal cord injury. Here we used agonists that are efficient in promoting locomotor recovery in paraplegic rats, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT) (acting on 5-HT1A/7 receptors) and quipazine (acting on 5-HT2 receptors), to examine this issue. Analysis of intra- and interlimb coordination confirmed that the locomotor performance was significantly improved by either drug, but the data revealed marked differences in their mode of action. Interlimb coordination was significantly better after 8-OHDPAT application, and the activity of the extensor soleus muscle was significantly longer during the stance phase of locomotor movements enhanced by quipazine. Our results show that activation of both receptors facilitates locomotion, but their effects are likely exerted on different populations of spinal neurons. Activation of 5-HT2 receptors facilitates the output stage of the locomotor system, in part by directly activating motoneurons, and also through activation of interneurons of the locomotor central pattern generator (CPG). Activation of 5-HT7/1A receptors facilitates the activity of the locomotor CPG, without direct actions on the output components of the locomotor system, including motoneurons. Although our findings show that the combined use of these two drugs results in production of well-coordinated weight supported locomotion with a reduced need for exteroceptive stimulation, they also indicate that there might be some limitations to the utility of combined treatment. Sensory feedback and some intraspinal circuitry recruited by the drugs can conflict with the locomotor activation.

Highlights

During the last few decades the potential role of 5-HT in locomotor system activation, modulation and functional recovery after spinal cord lesions has received considerable attention and continues to be an area of major interest and investigation
We have previously described improvement in locomotion produced by quipazine and 8-OHDPAT (Jordan and Sławinska, 2011; Sławinska et al, 2012b), but here we provide a comparison of the effects of these two agonists, and show how these data reveal aspects of the organization of the locomotor system that are influenced by serotonin receptor activation that have not previously been appreciated
Activation of 5-HT7 and 5-HT1A receptors that led to improved left-right alternation in hindlimb walking probably facilitated the activity of the locomotor central pattern generator (CPG), without direct actions on the output components of the locomotor system, including motoneurons

Summary

Introduction

During the last few decades the potential role of 5-HT in locomotor system activation, modulation and functional recovery after spinal cord lesions has received considerable attention and continues to be an area of major interest and investigation (reviewed in Hochman et al, 2001; Jordan and Schmidt, 2002; Orsal et al, 2002; Jordan and Sławinska, 2011). Using the in vitro neonatal rat spinal cord preparation it was demonstrated that 5-HT application induces locomotor-like discharge of lumbar ventral roots (Kudo and Yamada, 1987; Cazalets et al, 1990, 1992; Sqalli-Houssaini et al, 1993; Cowley and Schmidt, 1994; Kiehn and Kjaerulff, 1996), the frequency of which was concentration-dependent (Cazalets et al, 1992; Beato et al, 1997). The selective application of 5-HT on different spinal cord levels in this preparation using the bath partitioning method confirmed that the 5-HT-sensitive oscillatory network, capable of producing a locomotor-like pattern of activity, is diffusely distributed throughout the supralumbar spinal cord and mediates descending rhythmic drive to lumbar motor centers (Cowley and Schmidt, 1994, 1997; Schmidt and Jordan, 2000). A number of serotonergic receptors are found in the spinal cord, but 5-HT2A, 5-HT2C and 5-HT7

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