The chemokine stromal cell-derived factor-1/CXCL12 activates the nigrostriatal dopamine system.
We recently demonstrated that dopaminergic (DA) neurons of the rat substantia nigra constitutively expressed CXCR4, receptor for the chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 (SDF-1). To check the physiological relevance of such anatomical observation, in vitro and in vivo approaches were used. Patch clamp recording of DA neurons in rat substantia nigra slices revealed that SDF-1 (10 nmol/L) induced: (i) a depolarization and increased action potential frequency; and (ii) switched the firing pattern of depolarized DA neurons from a tonic to a burst firing mode. This suggests that SDF-1 could increase DA release from neurons. Consistent with this hypothesis, unilateral intranigral injection of SDF-1 (50 ng) in freely moving rat decreased DA content and increased extracellular concentrations of DA and metabolites in the ipsilateral dorsal striatum, as shown using microdialysis. Furthermore, intranigral SDF-1 injection induced a contralateral circling behavior. These effects of SDF-1 were mediated via CXCR4 as they were abrogated by administration of a selective CXCR4 antagonist. Altogether, these data demonstrate that SDF-1, via CXCR4, activates nigrostriatal DA transmission. They show that the central functions of chemokines are not restricted, as originally thought, to neuroinflammation, but extend to neuromodulatory actions on well-defined neuronal circuits in non-pathological conditions.
Skrzydelski
D
D
Institut National de la Santé et de la Recherche Médicale (INSERM) U 732, Université Pierre et Marie Curie-Paris 6, Hôpital Saint-Antoine, Paris Cedex, France.
Guyon
A
A
Daugé
V
V
Rovère
C
C
Apartis
E
E
Kitabgi
P
P
Nahon
J L
JL
Rostène
W
W
Parsadaniantz
S Mélik
SM
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality; D008297:Male; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C515356:Ccr4 protein, rat; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine