| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1Laval University Medical Centre; and 2Department of Anatomy and Physiology, Laval University, Quebec City, Canada
Submitted 7 March 2008; accepted in final form 7 May 2008
 |
ABSTRACT |
|---|
|
|
|
INTRODUCTION |
|---|
|
; Grillner and Zangger 1979). Often referred to as the central pattern generator (CPG), this network—located for the most part in the lumbar spinal cord—was reported indeed to produce locomotor-like activity following systemic administration of levodopa (L-DOPA; L-3,4-dihydroxyphenylalanine) and nialamide (noradrenergic/dopaminergic precursor and monoamine oxidase inhibitor, respectively) in the complete absence of input from the brain and the periphery (low-thoracic–transected and rhizotomized cats; Grillner and Zangger 1979). Shortly after that discovery, a plethora of substances tested in acute or chronic paraplegic cats have provided data suggesting that several monoaminergic systems are involved in the control of locomotion (reviewed in Rossignol et al. 2001). Along this line of evidence, a role for monoaminergic neurotransmitters in locomotor functions was strongly supported by Gerin et al. (1995) who showed, using spinal cord–implanted microdialysis probes and chromatography, an increase of dopamine (DA) and serotonin (5-HT) release in the ventral funiculus (lumbar segments) of animals running on a motor-driven treadmill.
In the 1990s, compelling evidence mainly from in vitro isolated spinal cord preparations has suggested that synergistic actions on CPG neurons can be achieved by coactivating different families of transmembranal receptors. For instance, bath-applied 5-HT, DA, and/or N-methyl-D-aspartate (NMDA) were reported to potently induce stable fictive locomotor rhythms in in vitro isolated spinal cord preparations (rats: Cazalets et al. 1992; Kiehn and Kjaerulff 1996; Kjaerulff et al. 1994; mice: Jiang et al. 1999; Whelan et al. 2000; lampreys: Zhang and Grillner 2000).
Some of these results were recently confirmed in vivo using spinal cord–transected (Tx) models. For instance, quipazine (5-HT2 agonist) and L-DOPA were found to generate greater effects on hindlimb movement induction when coadministered in Tx rats (McEwen et al. 1997) and mice (Guertin 2004a; Landry and Guertin 2004). Quipazine-induced air-stepping was found to critically depend on glutamate receptor activation (i.e., endogenous glutamate release since blocked by MK-801) in Tx mice (Guertin 2004b). D1/5 (D1-like) receptor agonists (but not D2-like or D2/3/4 agonists) were shown to specifically induce locomotor-like movements (LMs) in complete paraplegic mice (Lapointe and Guertin 2005; unpublished data). Most recently, 5-HT1A/7 ligands and 5-HT7 knockout (5-HT7–/–) mice were used to demonstrate a specific role in LM induction for both receptor subtypes (i.e., 5-HT1A and 5-HT7) in Tx animals (Landry et al. 2006a). However, it remains unclear whether simultaneously activating some of these specific receptor subtypes in vivo may lead to synergistic actions on CPG activation and hindlimb movement induction. Given that 5-HT1A/7 and D1/5 receptor agonists tested separately were found recently, in both in vitro and in vivo experiments, to display potent CPG-activating effects, we decided to assess their effects as a combination treatment on hindlimb movement generation in Tx mice.
The present series of experiments aimed at determining in vivo whether D1-like and 5-HT1A/7 receptors may synergistically induce stepping. Drug-induced movements were assessed in complete Tx mice tested on a motorized treadmill (moving at 8–10 cm/s) prior to and 15–20 min after drug administration. Comparisons were made between three main groups (D1/5-treated group; 5-HT1A/7-treated group; D1/5 + 5-HT1A/7-treated group) to clearly determine whether significantly greater effects may be induced by these selective agonists used in combination rather than separately. Preliminary results have been reported in abstract form (Lapointe and Guertin 2007).
|
|
METHODS |
|---|
|
This work was performed in accordance with the Canadian Guide for the Care and Use of Laboratory Animals. All procedures were approved by the Animal Research Committee of the Laval University Medical Centre. Experiments were carried out on male CD1 mice (n = 40; Charles River Laboratories, Montreal, Quebec) weighing 30–35 g at the time of surgery. Mice were housed generally four or five per cage in a temperature-controlled environment maintained under a 12-h light/dark cycle with free access to water and food (Teklab global 18% protein rodent diet 2018; Harlan Teklab, Madison, WI). Preoperative care included injections 30 min prior to surgery of lactate-Ringer solution (1.0 ml, administered subcutaneously [sc]), an antibiotic (Baytril; 5 mg/kg, sc; Bayer, Toronto, Ontario), and an analgesic (buprenorphine; 0.1 mg/kg, sc; Schering-Plough, Pointe-Claire, Quebec). The surgery was performed under general anesthesia with isoflurane (2.5%) as described elsewhere (Guertin 2005; Lapointe et al. 2006; Ung et al. 2007). Briefly, a nonlaminectomy complete spinal cord transection (Tx) was performed using microscissors inserted between the ninth and tenth thoracic vertebrae. The inner vertebral walls were then entirely scraped with scissor tips to sever any remaining fibers that had not been previously cut. The opened skin area was sutured and animals were placed on heating pads for a few hours. Postoperative care included daily injections of lactate-Ringer solution (2 x 1.0 ml, sc), buprenorphine (2 x 0.1 mg/kg, sc), and Baytril (5 mg/kg, sc) for four consecutive days. Bladders were manually expressed twice a day until testing (at 6 days post-Tx). Full transection was confirmed by postmortem histological analyses (i.e., staining longitudinal or coronal sections with luxol fast blue/cresyl violet). Only animals with a histologically confirmed complete Tx were kept for analyses.
Drug treatments
All treatments were performed at 6 days post-Tx to allow reasonable time for the animals to recover from surgery before behavioral testings. A first group of mice (n = 20) received either 0.25 (n = 5), 0.5 (n = 5), 1.0 (n = 5), or 2.0 mg/kg (n = 5) of 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine hydrobromide (SKF-81297) to establish its threshold for LM induction. Another group of animals (n = 6) was pretreated with SCH 23390 (potent D1/5 antagonist, 1 mg/kg) 15 min prior to SKF-81297 administration to confirm D1/5-mediated effects induced by SKF-81297. The lowest effective dose (0.5 mg/kg) of 8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT, selective 5-HT1A/7 receptor agonist) was chosen based on recent data from this laboratory (Landry et al. 2006a). As with SKF-81297, 8-OH-DPAT was also administered separately in a group of Tx mice (n = 9) to characterize in this study its effects at the lowest effective dose. A last group of animals (n = 5) received the combination treatment with the lowest effective doses of SKF-81297 (determined in this study to be 1–2 mg/kg; see Fig. 1) and 8-OH-DPAT (0.5 mg/kg; Landry et al. 2006a). All drugs were administered intraperitoneally and purchased from Tocris (Ellisville, MO). 8-OH-DPAT was diluted in sterile water, whereas SKF-81297 was first dissolved in dimethylsulfoxide (DMSO) and then diluted in sterile water to obtain a solution of 2% (vol/vol) DMSO in water. This dose of DMSO was found not to interfere with locomotor rhythmogenesis (unpublished observations).
|
Drug-induced effects were assessed in Tx mice placed on a motorized treadmill moving at 8–10 cm/s. A harness placed around the torso was used to maintain the animals in front of the camera (placed sideways). However, no body weight support assistance or other forms of stimulation (e.g., tail pinching) was provided to minimize variability and avoid unrelated (or unnatural) sensory input–mediated drug-induced effects. Hindlimb movements were monitored using a digital videocamera system (Sony DCR110, acquisition: 30 frames/s, shutter speed: 1/4,000) during 4 min immediately prior to and 15–20 min after drug administration. Two methods designed specifically to assess hindlimb movement in complete Tx rodents were used. The first method called average combined score (ACOS) (Guertin 2005; Lapointe et al. 2006; Ung et al. 2007) is a semiquantitative approach developed in this laboratory to assess essentially the frequency (number/min) of nonlocomotor movements (NLMs) and locomotor-like movements (LMs) as well as their amplitude and incidence. In brief, one NLM is defined as a unilateral movement (e.g., fast paw shaking, twitch, cramp, jerk, or any other nonbilaterally coordinated movements), whereas one LM is defined as a flexion followed by an extension (or vice versa) occurring in both hindlimbs in alternation (a bilaterally alternating locomotor-like movement). Movement amplitude was reported as small or large and given the arbitrary numerical value of 1 or 2, respectively. Movement incidence is defined as the number of animals in which NLMs or LMs were observed. ACOS scores were obtained by arithmetically combining these values as follows: 
{(NLM/min) + [(LM/min) x 2]} x amplitude
(Guertin 2005). The presence of weight-bearing and plantar foot placement capabilities was also examined and reported separately.
A second assessment method developed by Antri, Orsal, and Barthe (AOB; Antri et al. 2002) was also used. As with the ACOS method, this AOB scale has been specifically designed to assess hindlimb movement induced by CPG-activating compounds in complete paraplegic rodents. Briefly, it is a scale including 22 discriminating scores, mainly grouped into four categories or levels. The first level (scores 0 and 1) reports either the absence of movement or the presence of small amplitude jerks. The second level (scores 2–9) includes rhythmic locomotor-like movements accompanied of dorsal foot placement. The third level (score 10) is associated with the occurrence of large-amplitude locomotor-like movements with dorsal foot placement and occasional body weight support. Finally, the last level (scores 11–22) reports movements accompanied by plantar foot placement and body weight support. For additional details, see Antri et al. (2002).
Statistical analyses
Paired t-tests were used to compare pre- vs. postinjection data. Comparisons between groups were performed with one-way ANOVAs followed by Tukey's post hoc tests when significant. All analyses were done using SPSS 11.0 (Chicago, IL). Results are expressed as means ± SE. Values of P < 0.05 were deemed statistically significant.
|
|
RESULTS |
|---|
|
A first group of mice (n = 20) received either 0.25, 0.5, 1.0, or 2.0 mg/kg to establish the lowest effective dose of SKF-81297 for inducing LMs. As shown elsewhere (Guertin 2005; Lapointe et al. 2006) and throughout this study, no LMs but occasional NLMs (reflex-induced) were typically found to spontaneously occur with no drug treatment in 1-wk Tx animals (see preinjection conditions; white bars in Fig. 1, A and B). We found in this study that administration of SKF-81297 induced within 15 min a dose-dependent increase of NLMs (reported as numbers of NLM/min). Indeed, although essentially no NLM was found in the 0.25 mg/kg-treated group, generally significant (#P = 0.06, although the data were not significant, there was a possibility of a false-negative finding because the power was low, **P < 0.01) values were obtained in the 1.0 mg/kg-treated (6.30 ± 2.30) and 2.0 mg/kg-treated groups (12.40 ± 1.28), respectively (black bars, Fig. 1A). Although absolutely no LM was found to spontaneously occur prior to drug administration (Fig. 1B, white bars), generally significant (#P = 0.06 or **P < 0.01) numbers of LM were found only at 1.0 mg/kg (4.70 ± 2.27) and 2.0 mg/kg (7.00 ± 0.94) (black bars, Fig. 1B). Comparable results were obtained using the corresponding ACOS (>27 at 1.0 mg/kg) and AOB scores (>4 at 1.0 mg/kg), clearly showing that the lowest effective dose of SKF-81297 for inducing significant hindlimb movements (reported either as NLM, LM, ACOS, or AOB scores) was between 1 and 2 mg/kg. Consequently, we used 1 or 2 mg/kg SKF-81297 (equal number of animals tested with each dose) in each subsequent test.
To confirm whether SKF-81297–induced effects (at 1 and 2 mg/kg) were indeed mediated by the D1/5 receptors, we administered 1 or 2 mg/kg SKF-81297 in another group of animals (n = 6) pretreated 15 min earlier with a selective D1/5 receptor antagonist called SCH 23390 (1.0 mg/kg). Figure 2 shows that a significant (P < 0.001) reduction of LM and NLM was found following administration of SKF-81297 in the SCH 23390–pretreated group compared with controls. In fact, the relatively low NLM, LM, ACOS, and AOB values and scores found in the SCH 23390–pretreated group that received SKF-81297 (dark gray bars) were not dissimilar (P > 0.05) from those found preinjection (Fig. 2, white bars) or just prior to SKF-81297 administration (SCH 23390 only; Fig. 2, pale gray bars).
|
The lowest effective dose of 8-OH-DPAT (a 5-HT1A/7 receptor agonist) for inducing LM has been found previously to be <1.0 mg/kg (Landry et al. 2006a). In addition, Landry et al. (2006a) clearly established that these effects completely disappeared in animals pretreated with the corresponding receptor antagonists (WAY100135 and SB269970), thus providing strong evidence of 5-HTR1A–and 5-HTR7–mediated effects. Here, we found that 0.5 mg/kg 8-OH-DPAT induced some hindlimb movements that were comparable with those described earlier, elicited by 1 mg/kg SKF-81297. 8-OH-PAT (0.5 mg/kg, ip) generated occasional but significant (P < 0.05) numbers of LM (3.67 ± 1.44; P < 0.05) and NLM (9.29 ± 2.73; P < 0.05; Fig. 3D). LM and NLM were found in, respectively, 67 and 89% of the treated mice (Fig. 3E, corresponding incidence values). Although only small-amplitude movements were found (±1, Fig. 3D), 8-OH-DPAT–induced effects corresponded to a significant increase (P < 0.05 and P < 0.01, respectively) of ACOS and AOB scores postinjection versus preinjection (black bars vs. white bars; Fig. 3, E and F). In turn, no incidence of weight-bearing stepping (WBS) or plantar foot placement (PFP) was found at 0.5 mg/kg in this study (Fig. 3F) or elsewhere with higher doses of 8-OH-DPAT (0.25–2.0 mg/kg; Landry et al. 2006a). As with 8-OH-DPAT, only small-amplitude movements (±1) with no WBS and rare PFP placement (i.e., found occasionally in three of nine mice; see Fig. 3C vs. Fig. 3B) were also induced by the lowest effective dose of SKF-81297.
|
A last group of Tx animals (n = 5) received instead a coinjection of selective D1/5 and 5-HT1A/7 receptor agonists. As illustrated in Fig. 4, simultaneous administration of the lowest effective doses of SKF-81297 (1 or 2 mg/kg) and 8-OH-DPAT (0.5 mg/kg) elicited a 7- to a 10-fold increase in hindlimb movement generation. This combination induced significant (P < 0.01) numbers of LM (37.70 ± 5.01 LM/min) and NLM (8.30 ± 0.78 NLM/min) postinjection versus preinjection (Fig. 4A, black bars vs. white bars, respectively). Both NLM and LM of large amplitude (near 2) were found in all mice tested (incidence of 100%; Fig. 4, A and B). Correspondingly, the ACOS and AOB scores reached 167.40 ± 19.48 and 15.80 ± 0.80. In clear contrast with the effects obtained using both agonists separately (Figs. 1–3), this drug combination induced hindlimb movements that were accompanied of frequent-to-regular WBS and occasional-to-frequent PFP (Fig. 4C).
|
|
|
|
|
DISCUSSION |
|---|
|
Indeed, drug-induced stepping movements have been found in other models such as in adult Tx cats and rats, but always accompanied with other forms of stimulation/intervention including regular treadmill training, tail or perineal pinching, and body weight support assistance (e.g., in cats: Barbeau and Rossignol 1991; in rats: Antri et al. 2002, 2005). Another kind of intervention such as fetal neural tissue transplants combined with 5-HT2 agonists and regular treadmill training have also led to significant locomotor function recovery in young Tx rats (Kim et al. 1999). There is compelling evidence suggesting that these forms of assistance and stimulation have a significant influence over CPG activation. In fact, regular treadmill training itself has been shown to largely restore reflex stepping in complete Tx cats (in adult cats: Barbeau and Rossignol 1987; Lovely et al. 1986; in kittens: Forssberg et al. 1980). Tail pinching has been shown to play a critical role in spinal stepping generation. It is generally performed in most spinal cat studies (including those cited earlier) and was reported in untrained Tx cats to induce full weight-bearing stepping in treadmill condition (de Leon et al. 1998). Comparable effects were detected occasionally using tail stimulation in Tx mice (Leblond et al. 2003). Norreel et al. (2003) demonstrated that mechanical stimulation of the tail in spinal cord–transected neonatal rats could trigger episodes of air-stepping, whereas this type of stimulus was ineffective in sham-operated rats. A direct activation of CPG neurons by tail-related inputs is also supported by results from in vitro isolated spinal cords showing locomotor-like rhythms induced by sacrocaudal afferent stimulation (Strauss and Lev-Tov 2003). Another key factor that can affect CPG activation post spinal cord injury (SCI) is time. It is increasingly recognized that sublesional plasticity events that may affect CPG reorganization and excitability occur spontaneously within a few weeks to a few months post-SCI (e.g., see DISCUSSION in Landry et al. 2006b). For instance, it was shown without intervention (i.e., no grafts, drugs, training, or tail stimulation) that low but significant levels of hindlimb movements may spontaneously occur in mice within a few weeks post-Tx in open-field or treadmill conditions (Guertin 2005; Lapointe et al. 2006; Ung et al. 2007).
This said, it is likely that several types of sensory input have nonetheless contributed to the potent effects reported in this study. For instance, sensory inputs associated with the foot and the rest of the leg rubbing against the running treadmill belt (8–10 cm/s) could have contributed to spinal stepping induction. This is supported by earlier data from this laboratory showing greater (higher frequency) hindlimb movements (both LM and NLM) following SR57227A (a 5-HT3 agonist) administration in treadmill condition than in open-field or air-stepping conditions (Guertin and Steuer 2005). Cycling inputs from the hip joint may also have contributed to entrain cyclic changes and rhythms, as elegantly shown several years ago in Tx cats (Andersson and Grillner 1983; Grillner and Rossignol 1978). Group I afferent inputs from extensors could also have participated to augment contractions in homonymous and heteronymous extensor muscles during the extension phase (Guertin et al. 1995).
Mechanistically, compelling evidence indicates that these effects specifically involved an activation of 5-HT1A, 5-HT7, and D1 receptors. As mentioned earlier, bath-applied 5-HT, DA, and/or NMDA was found to potently induce stable fictive locomotor rhythms in in vitro isolated spinal cord preparations (rats: Cazalets et al. 1992; Kiehn and Kjaerulff 1996; Kjaerulff et al. 1994; mice: Gordon and Whelan 2006; Jiang et al. 1999; Whelan et al. 2000; lampreys: Zhang and Grillner 2000). A specific role in CPG activation for only a subset of receptors has also been suggested by data from in vitro experiments. For example, selective D1-like (D1 and D5) agonists (but not D2-like agonists) were found to produce effects (inducing or modulating) comparable to those found with DA on spinal rhythms in rat isolated spinal cord preparations (Barrière et al. 2004). 5-HT1A receptor agonists (but not 5-HT2 agonists) were also reported to reversibly (blocked by corresponding antagonists) elicit rhythms and cellular effects comparable to those found with 5-HT in the lamprey spinal cord model (Wikstrom et al. 1995; Zhang and Grillner 2000). Evidence suggesting a role in spinal rhythm generation for other receptor subtypes such as the 5-HT2A and 5-HT7 has also been reported (Liu and Jordan 2005; Madriaga et al. 2004).
Some of these results have been confirmed in vivo. The D1 receptor was shown, using selective ligands and D5 knockout (D5–/–) animals, to specifically mediate LM induction in complete paraplegic mice (Lapointe and Guertin 2005; unpublished data). Indeed, LM induced by D1/5 agonists (but not D2/3/4 agonists) were detected in wild-type Tx mice as well as in D5–/– animals unless pretreated with D1/5 antagonists, strongly suggesting a specific role of the D1 subtype in spinal stepping generation (Lapointe and Guertin 2005; unpublished data). We have also recently found that 8-OH-DPAT–induced LMs in spinal Tx mice were completely blocked only after coadministration of selective 5-HT1A and 5-HT7 antagonists or in 5-HT7–/– pretreated with 5-HT1A antagonists, clearly suggesting that 8-OH-DPAT–induced locomotor-like movements critically depend on both receptor subtypes (i.e., 5-HT1A and 5-HT7; Landry et al. 2006a). It is worth mentioning that none of these experiments with 8-OH-DPAT or SKF-81297 used separately revealed self-sustained weight-bearing stepping (Landry et al. 2006a; Lapointe and Guertin 2005). Instead, prior to the present study, only some locomotor-like movements without weight-bearing or plantar foot placement capabilities (resembling crawling more than stepping) had been found with these ligands as well as with a number of others compounds administered separately or in combination [i.e., 5-HT3 agonists used separately or combined with 5-HT7 agonists (Guertin and Steuer 2005); L-DOPA alone or combined with 5-HT2A/2C agonists (Guertin 2004a); 5-HT2A/2C agonists alone or combined with NMDA (Guertin 2004b); 5-HT1B/2B/2C agonists used separately or combined with L-DOPA (Landry and Guertin 2004)].
In conclusion, this study reveals that 1–2 mg/kg SKF-81297 and 0.5 mg/kg 8-OH-DPAT administered separately can trigger some NLMs and LMs with no weight-bearing or plantar foot placement capabilities in spinal cord–transected mice. The main finding is that when combined using the same doses, these ligands can induce a 7- to 10-fold increase in LM generation (37.70 ± 5.01 LM/min) accompanied by significant weight-bearing and plantar foot placement. These synergistic effects were found in early paraplegic animals without other forms of assistance or stimulation (untrained, no tail pinching, no grafts, etc.), strongly suggesting the existence of CPG-mediated actions. Together with earlier work from our laboratory using selective antagonists and knockout animals (5-HT7–/– and D5–/–), the present finding strongly suggests the existence of a critical role for the 5-HT1A, 5-HT7, and D1 receptors in CPG activation and hindlimb stepping generation in vivo. This may pave the way to the development of novel pharmacological treatments aimed at promoting treadmill training in SCI patients.
|
|
GRANTS |
|---|
|
|
|
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: P. Guertin, Laval University Medical Centre, Neuroscience Unit, RC-9800, 2705, Laurier Blvd., Quebec City, Quebec, Canada G1V 4G2 (E-mail: pierre.guertin{at}crchul.ulaval.ca)
|
|
REFERENCES |
|---|
|
Antri M, Barthe JY, Mouffle C, Orsal D. Long-lasting recovery of locomotor function in chronic spinal rat following chronic combined pharmacological stimulation of serotonergic receptors with 8-OH-DPAT and quipazine. Neurosci Lett 384: 162–167, 2005.[CrossRef][Web of Science][Medline]
Antri M, Orsal D, Barthe JY. Locomotor recovery in the chronic spinal rat: effects of long-term treatment with a 5-HT2 agonist. Eur J Neurosci 16: 467–476, 2002.[CrossRef][Web of Science][Medline]
Barbeau H, Rossignol S. Recovery of locomotion after chronic spinalization in the adult cat. Brain Res 412: 84–95, 1987.[CrossRef][Web of Science][Medline]
Barbeau H, Rossignol S. Initiation and modulation of the locomotor pattern in the adult chronic spinal cat by noradrenergic, serotonergic and dopaminergic drugs. Brain Res 546: 250–260, 1991.[CrossRef][Web of Science][Medline]
Barrière G, Mellen N, Cazalets JR. Neuromodulation of the locomotor network by dopamine in the isolated spinal cord of newborn rat. Eur J Neurosci 19: 1325–1335, 2004.[CrossRef][Web of Science][Medline]
Brown TG. The intrinsic factors in the act of progression in the mammals. Proc R Soc Lond B Biol Sci 84: 308–319, 1911.[CrossRef][Web of Science]
Cazalets JR, Sqalli-Houssaini Y, Clarac F. Activation of the central pattern generators for locomotion by serotonin and excitatory amino acids in neonatal rat. J Physiol 455: 187–204, 1992.
de Leon RD, Hodgson JA, Roy RR, Edgerton VR. Locomotor capacity attributable to step training versus spontaneous recovery after spinalization in adult cats. J Neurophysiol 79: 1329–1340, 1998.
Forssberg H, Grillner S, Halbertsma J. The locomotion of the low spinal cat. I. Coordination within a hindlimb. Acta Physiol Scand 108: 269–281, 1980.[Web of Science][Medline]
Gerin C, Becquet D, Privat A. Direct evidence for the link between monoaminergic descending pathways and motor activity. I. A study with microdialysis probes implanted in the ventral funiculus of the spinal cord. Brain Res 704: 191–201, 1995.[CrossRef][Web of Science][Medline]
Gordon IT, Whelan PJ. Monoaminergic control of cauda-equina-evoked locomotion in the neonatal mouse spinal cord. J Neurophysiol 96: 3122–3129, 2006.
Grillner S, Rossignol S. On the initiation of the swing phase of locomotion in chronic spinal cats. Brain Res 146: 269–277, 1978.[CrossRef][Web of Science][Medline]
Grillner S, Zangger P. On the central generation of locomotion in the low spinal cat. Exp Brain Res 34: 241–261, 1979.[Web of Science][Medline]
Guertin P, Angel MJ, Perreault MC, McCrea DA. Ankle extensor group I afferents excite extensors throughout the hindlimb during fictive locomotion in the cat. J Physiol 487: 197–209, 1995.
Guertin PA. Synergistic activation of the central pattern generator for locomotion by l-beta-3,4-dihydroxyphenylalanine and quipazine in adult paraplegic mice. Neurosci Lett 358: 71–74, 2004a.[CrossRef][Web of Science][Medline]
Guertin PA. Role of NMDA receptor activation in serotonin agonist-induced air-stepping in paraplegic mice. Spinal Cord 42: 185–190, 2004b.[CrossRef][Web of Science][Medline]
Guertin PA. Semiquantitative assessment of hindlimb movement recovery without intervention in adult paraplegic mice. Spinal Cord 43: 162–166, 2005.[CrossRef][Web of Science][Medline]
Guertin PA, Steuer I. Ionotropic 5-HT3 receptor agonist-induced motor responses in the hindlimbs of paraplegic mice. J Neurophysiol 94: 3397–3405, 2005.
Jiang Z, Carlin KP, Brownstone RM. An in vitro functionally mature mouse spinal cord preparation for the study of spinal motor networks. Brain Res 816: 493–499, 1999.[CrossRef][Web of Science][Medline]
Kiehn O, Kjaerulff O. Spatiotemporal characteristics of 5-HT and dopamine-induced rhythmic hindlimb activity in the in vitro neonatal rat. J Neurophysiol 75: 1472–1482, 1996.
Kim D, Adipudi V, Shibayama M, Giszter S, Tessler A, Murray M, Simansky KJ. Direct agonists for serotonin receptors enhance locomotor function in rats that received neural transplants after neonatal spinal transection. J Neurosci 19: 6213–6224, 1999.
Kjaerulff O, Barajon I, Kiehn O. Sulphorhodamine-labelled cells in the neonatal rat spinal cord following chemically induced locomotor activity in vitro. J Physiol 478: 265–273, 1994.
Landry ES, Guertin PA. Differential effects of 5-HT(1) and 5-HT(2) receptor agonists on hindlimb movements in paraplegic mice. Prog Neuropsychopharmacol Biol Psychiatry 28: 1053–1060, 2004.[CrossRef][Medline]
Landry ES, Lapointe NP, Rouillard C, Levesque D, Hedlund PB, Guertin PA. Contribution of spinal 5-HT1A and 5-HT7 receptors to locomotor-like movement induced by 8-OH-DPAT in spinal cord-transected mice. Eur J Neurosci 24: 535–546, 2006a.[CrossRef][Web of Science][Medline]
Landry ES, Rouillard C, Levesque D, Guertin PA. Profile of immediate early gene expression in the lumbar spinal cord of low-thoracic paraplegic mice. Behav Neurosci 120: 1384–1388, 2006b.[CrossRef][Web of Science][Medline]
Lapointe N, Guertin P. Specific dopamine receptor subtypes associated with hindlimb movement generation in early paraplegic mice. Soc Neurosci Abstr 516.10, 2005.
Lapointe N, Guertin P. Powerful induction of locomotor-like movement in complete paraplegic mice following administration of D1/5 and 5-HT1A/7 receptor agonists. Soc Neurosci Abstr 289.5, 2007.
Lapointe NP, Ung RV, Bergeron M, Cote M, Guertin PA. Strain-dependent recovery of spontaneous hindlimb movement in spinal cord transected mice (CD1, C57BL/6, BALB/c). Behav Neurosci 120: 826–834, 2006.[CrossRef][Web of Science][Medline]
Leblond H, L'Esperance M, Orsal D, Rossignol S. Treadmill locomotion in the intact and spinal mouse. J Neurosci 23: 11411–11419, 2003.
Liu J, Jordan LM. Stimulation of the parapyramidal region of the neonatal rat brain stem produces locomotor-like activity involving spinal 5-HT7 and 5-HT2A receptors. J Neurophysiol 94: 1392–1404, 2005.
Lovely RG, Gregor RJ, Roy RR, Edgerton VR. Effects of training on the recovery of full-weight-bearing stepping in the adult spinal cat. Exp Neurol 92: 421–435, 1986.[CrossRef][Web of Science][Medline]
Madriaga MA, McPhee LC, Chersa T, Christie KJ, Whelan PJ. Modulation of locomotor activity by multiple 5-HT and dopaminergic receptor subtypes in the neonatal mouse spinal cord. J Neurophysiol 92: 1566–1576, 2004.
McEwen ML, Van Hartesveldt C, Stehouwer DJ. L-DOPA and quipazine elicit air-stepping in neonatal rats with spinal cord transections. Behav Neurosci 111: 825–833, 1997.[CrossRef][Web of Science][Medline]
Norreel JC, Pflieger JF, Pearlstein E, Simeoni-Alias J, Clarac F, Vinay L. Reversible disorganization of the locomotor pattern after neonatal spinal cord transection in the rat. J Neurosci 23: 1924–1932, 2003.
Rossignol S, Giroux N, Chau C, Marcoux J, Brustein E, Reader TA. Pharmacological aids to locomotor training after spinal injury in the cat. J Physiol 533: 65–74, 2001.
Strauss I, Lev-Tov A. Neural pathways between sacrocaudal afferents and lumbar pattern generators in neonatal rats. J Neurophysiol 89: 773–784, 2003.
Ung RV, Lapointe NP, Tremblay C, Larouche A, Guertin PA. Spontaneous recovery of hindlimb movement in completely spinal cord transected mice: a comparison of assessment methods and conditions. Spinal Cord 45: 367–379, 2007.[Web of Science][Medline]
Whelan P, Bonnot A, O'Donovan MJ. Properties of rhythmic activity generated by the isolated spinal cord of the neonatal mouse. J Neurophysiol 84: 2821–2833, 2000.
Wikstrom M, Hill R, Hellgren J, Grillner S. The action of 5-HT on calcium-dependent potassium channels and on the spinal locomotor network in lamprey is mediated by 5-HT1A-like receptors. Brain Res 678: 191–199, 1995.[CrossRef][Web of Science][Medline]
Zhang W, Grillner S. The spinal 5-HT system contributes to the generation of fictive locomotion in lamprey. Brain Res 879: 188–192, 2000.[CrossRef][Web of Science][Medline]
This article has been cited by other articles:
|
|
 |
|
  B. R. Noga, D. M. G. Johnson, M. I. Riesgo, and A. Pinzon Locomotor-Activated Neurons of the Cat. I. Serotonergic Innervation and Co-Localization of 5-HT7, 5-HT2A, and 5-HT1A Receptors in the Thoraco-Lumbar Spinal Cord J Neurophysiol, September 1, 2009; 102(3): 1560 - 1576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. P. Lapointe, P. Rouleau, R.-V. Ung, and P. A. Guertin Specific role of dopamine D1 receptors in spinal network activation and rhythmic movement induction in vertebrates J. Physiol., April 1, 2009; 587(7): 1499 - 1511. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
TOP
ABSTRACT
INTRODUCTION
