The role of serotonin in reflex modulation and locomotor rhythm production in the mammalian spinal cord
Introduction
The possibility that aminergic mechanisms may have a role in mammalian spinal motor control emerged after the demonstration of bulbospinal monoamine systems in the 1960s 9, 56, 57, 88, 89, 236. Interestingly, these early experiments included the use of an in vitro mammalian spinal cord to show serotonin (5-HT) release in response to electrical stimulation 5, 6, two decades before this preparation was popularized by Kudo and Yamada [208] and Smith and Feldman [339] for the study of locomotion. Over the past 13 years, the neonatal rat in vitro spinal cord model has proven to be a powerful instrument for examining the neurochemical substrate of locomotor networks in mammals.
Our focus on 5-HT is not intended to suggest that no other monoamines are involved in the activation or modulation of locomotor circuitry. In fact, there is ample evidence to the contrary (e.g., 25, 60, 61, 122, 181, 182, 186, 196, 197, 199). However, 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.
A recent review of the rapidly evolving subject of 5-HT receptor distribution, structure and pharmacology is provided by Barnes and Sharp [27]. The following discussion is limited to 5-HT actions in the mammalian spinal cord with an emphasis on the modulation of reflexes and locomotor networks. Where relevant, observations obtained from some of the non-mammalian literature are also cited. Within the scope of this review, we do not attempt to address the extensive literature on serotonergic modulation of pain pathways, spinal autonomic systems, or respiration.
Section snippets
Origin of 5-HT in the spinal cord
The anatomy and development of neuronal projections to the rat spinal cord, including 5-HT fibers, has been reviewed in detail elsewhere (see [210]). Only those observations most relevant to spinal reflexes and locomotor systems are highlighted here.
Almost all 5-HT in the rat spinal cord originates supraspinally 56, 57 from cells located in three of the nine 5-HT-containing brainstem regions described by Dahlstrom and Fuxe [88]. These projections descend from the medullary raphe pallidus (B1),
Maturation of bulbospinal serotonergic projections and role in development
Rat raphe cells are generated between embryonic days 11 and 15 (E11 and E15) [210]. The axons of 5-HT-containing neurons enter the cervical cord, via the ventral and lateral funiculi, at E13–14 and a few fibers begin to reach the lumbar cord by E15–16 207, 306, 398. Invasion of the anterior horn and intermediolateral column by 5-HT axon collaterals, or sharp angulation of axons, starts in the cervical and upper thoracic levels at E15, with more profuse innervation at these levels being present
5-HT receptor distribution and maturation in the spinal cord
Initial autoradiographic studies of 5-HT receptors in the mammalian spinal cord reported multiple 5-HT1 subtypes but failed to detect 5-HT2 receptors [262]. Subsequent investigations demonstrated 5-HT2 receptors, but a generally higher density of 5-HT1 receptors. 5-HT1 receptors dominate the dorsal horn whereas 5-HT2 receptors are found mainly in the ventral horn and intermediolateral nucleus 117, 120, 135, 174, 241, 261, 291, 292, 293, 297, 303, 356. Similar to the rostrocaudal gradient of
Historical overview
Beginning in 1955, several reports suggested 5-HT had an influence on segmental reflex activity in the spinal cord 86, 201, 202, 225, 338. However, initial studies involving iontophoretically applied tryptamines on spinal cord neurons produced negative results leading to the conclusion, in 1962, that tryptamine receptors were not likely to be of much significance with respect to synaptic transmission in the spinal cord 85, 87. Marley and Vane [238] suggested the negative results were related to
In vivo studies—cat and rabbit
In 1967, Jankowska and colleagues provided the first evidence that monoamines may have a role in the generation of locomotion when they showed that intravenous L-3,4-dihydroxyphenylalanine (L-DOPA) administration to acute spinal cats evoked rhythmic alternating discharge in flexor and extensor efferents 181, 182. Two years later, Viala and Buser reported that intravenous 5-HTP administration to lightly anesthetized, paralyzed rabbits with intact nervous systems facilitated the locomotor-like
5-HT facilitates the expression of plateau potentials
Plateau potentials are slow regenerative depolarizations typically lasting longer than sodium spikes [145]. Plateau properties have been examined extensively in cat and turtle spinal motoneurons 77, 84, 102, 103, 164, 165, 166, 167, 168, 169, 170, 171, 194, 221, 222, 289, 313, 314, 315, 324, 337, 349, 350 and have been postulated to help shape motor output during locomotion ([for review, see [193]). Plateau potentials in motoneurons are a latent property; 5-HT facilitates their expression 84,
Role of 5-HT in regeneration and recovery of motor function
The observation that 5-HT modulates, and in some cases initiates, locomotion in spinalized animals suggests that therapeutic interventions aimed at augmenting 5-HT levels in the spinal cord, caudal to a lesion, may have a beneficial effect on recovery of locomotor function.
One experimental approach using this strategy has been to transplant 5-HT-containing neurons from the embryonic brainstem into the spinal cord of adult rats, below the level of the transection or compression injury 116, 123,
Summary
This review has outlined the complex and sometimes competing array of effects 5-HT has on spinal cord reflexes and locomotor function. However, a consistent theme is that 5-HT helps shape the pattern of motor output. This observation is consistent with the hypothesis forwarded by Jacobs and Fornal, which states that the primary function of 5-HT is to facilitate motor output and inhibit sensory input [179]. Hopefully, further research and a more detailed understanding of the role of 5-HT and
Acknowledgements
We wish to thank Drs. Brent Fedirchuk and Doreen Fyda for their assistance in providing the data shown in Fig. 4, and Dr. Susan Shefchyk for her valuable comments. This work was supported by the Medical Research Council of Canada.
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