Specific role of dopamine D1 receptors in spinal network activation and rhythmic movement induction in vertebrates

Abstract

Dopamine (DA) is well-recognized for its determinant role in the modulation of various brain functions. DA was also found in in vitro isolated invertebrate preparations to activate per se the central pattern generator for locomotion. However, it is less clear whether such a role as an activator of central neural circuitries exists in vertebrate species. Here, we studied in vivo the effects induced by selective DA receptor agonists and antagonists on hindlimb movement generation in mice completely spinal cord-transected (Tx) at the low-thoracic level (Th9/10). Administration of D1/D5 receptor agonists (0.5-2.5 mg kg −1 , i.p.) was found to acutely elicit rhythmic locomotor-like movements (LMs) and non-locomotor movements (NLMs) in untrained and non-sensory stimulated animals. Comparable effects were found in mice lacking the D5 receptor (D5KO) whereas D1/D5 receptor antagonist-pretreated animals (wild-type or D5KO) failed to display D1/D5 agonist-induced LMs. In contrast, administration of broad spectrum or selective D2, D3 or D4 agonists consistently failed to elicit significant hindlimb movements. Overall, the results clearly show in mice the existence of a role for D1 receptors in spinal network activation and corresponding rhythmic movement generation.

Dopaminergic modulation of locomotor network activity in the neonatal mouse spinal cord

“…Over the past decade, work in vivo has implicated an important role for dopamine in generating and maintaining stepping behavior (Gerin and Privat 1998;Jordan and Schmidt 2002;Lapointe et al 2009;McCrea et al 1997). Additionally, in vitro work has highlighted the ability of dopamine to modulate ongoing locomotor rhythms in several vertebrate species (Barrière et al 2004;Clemens et al 2012;Gordon and Whelan 2006;Jiang et al 1999;Madriaga et al 2004;Schotland et al 1995;Whelan et al 2000).…”

“…What we do know is that dopamine is released within the spinal cord during stepping activity (Gerin and Privat 1998;Jordan and Schmidt 2002) to alter motor output (Barbeau and Rossignol 1991;Clemens et al 2012;Han et al 2007;Han and Whelan 2009;Lapointe et al 2009;Madriaga et al 2004;McCrea et al 1997) and modulate sensory transmission in a variety of species. Dopaminergic fibers project from the diencephalon (A11 area), and all five dopamine receptors are present in the ventral horn of the adult mouse spinal cord (Holstege et al 1996;Qu et al 2006;Ridet et al 1992;Weil-Fugazza and Godefroy 1993;Yoshida and Tanaka 1988;Zhu et al 2007), where motor circuits are located.…”

“…The key role for dopaminergic transmission in locomotion is highlighted by the fact that L-DOPA-elicited air stepping in intact neonatal rats is blocked by D 1 -like and D 2 -like receptor antagonists (McCrea et al 1997) and that D 1 agonists can promote stepping in adult mice (Lapointe et al 2009). Additionally, previous work has emphasized that dopamine can modulate ongoing drug-evoked locomotor rhythms and in rats can even evoke locomotor-like activity (Barrière et al 2004;Humphreys and Whelan 2012;Jiang et al 1999;Madriaga et al 2004;Milan et al 2014;Schotland et al 1995;Whelan et al 2000).…”

Mechanisms contributing to the dopamine induction of crawl-like bursting in leech motoneurons

“…Dopamine (DA) is known to play an impressive and universal role in the control of animal movements, often by exerting prolonged changes in the patterns of activity of locomotor-related neural networks (Chandler and Goldberg, 1984;Flamm and Harris-Warrick, 1986;Kemnitz, 1997;Lapointe et al, 2009;Quinlan et al, 1997;Teyke et al, 1993). In the medicinal leech, for example, DA has been shown to activate the central pattern generator (CPG) underlying crawling behavior (Puhl and Mesce, 2008;Puhl and Mesce, 2010).…”

Key central pattern generators of the spinal cord

“…This said, other alpha-2 agonists such as tizanidine were found occasionally to trigger some locomotor-like movements in Tx mice, possibly suggesting nonsignificant I1-mediated actions (unpublished observations). With regard to DA receptor agonists, administration of D2, D3, or D4 agonists failed to generate significant hindlimb movements, whereas D1/D5 agonists such as SKF-81297 potently elicited locomotorlike movements in Tx mice (Lapointe et al, 2009). Knockout animals (D5KO) and pretreatments with selective antagonists clearly established D1 receptor-mediated locomotor-like effects (Lapointe et al, 2009).…”