« Dopamine function in the spinal cord: its modulatory actions and its relation to restless legs syndrome »
Soutenue le 07 mars 2011
The hypothalamus controls autonomic nervous system function in a large part via strong descending projections to sympathetic preganglionic neurons in the intermediolateral nucleus (IML) of the thoraco-lumbar spinal cord, including dopaminergic fibers from the A11 region. The A11 region provides the only dopamine (DA) input to the cord, and DA directly inhibits IML neurons thus limiting sympathetic NS activity. In fact, many spinal cord-injured individuals, presumably with impaired DA projections, express an excess sympathetic activation (e.g. autonomic dysreflexia). DA dysfunction is also likely involved in Restless Legs Syndrome (RLS), a common sleep disorder with a strong circadian profile, but the mechanisms are still unknown.
Dopamine regulates the excitability of monosynaptic and polysynaptic reflex pathways in the thoraco-lumbar cord, and this modulation is governed in particular via D3 receptor pathways. Moreover, in animals lacking the D3 receptor (D3KO), the DA-induced depression of the reflex is converted into facilitation. Since D3 receptor agonists are particular successful in treating and relieving RLS, these data suggest that a dysfunction of the D3 receptor signaling pathways might be crucial for the pathophysiological symptoms observed in the clinic. Taken together, our data indicate that descending DA projections in the spinal cord are under circadian control and that they have important functional consequences on spinal networks both with regard to the somatic nervous system, as well as to the common output center of the autonomic nervous system.
S. Clemens, D.B. Rye, and S. Hochman (2006)
Restless Legs Syndrome: Revisiting the dopamine hypothesis from the spinal cord perspective, Neurology, in press
S. Clemens, M.A. Sawchuk, and S. Hochman (2005)
Reversal of the circadian expression of tyrosine-hydroxylase but not nitric oxide synthase levels in the spinal cord of D3 receptor knockout mice, Neuroscience, 133(2)353-357
S. Clemens and S. Hochman (2004)
Conversion of the Modulatory Actions of Dopamine on Spinal Reflexes from Depression to Facilitation in D3 Receptor knockout mice, Journal of Neuroscience 24:11337-11345
- Denis Combes, Professeur Universite Bordeaux (président)
- Ansgar Büschges, Professeur Universite Cologne
- Francois Clarac, Directeur de recherches CNRS, Marseille
- Imad Ghorayeb, MCU et Practicien Hosp, Universite Bordeaux
- Daniel Zytnicki, Directeur de recherches CNRS, Marseille