chemokine stromal cell-derived factor-1/CXCL12 activates the nigrostriatal dopamine system

• Published in: Journal of neurochemistry 2007-08, Vol.102 (4), p.1175-1183
• Main Authors: Skrzydelski, D, Guyon, A, Daugé, V, Rovère, C, Apartis, E, Kitabgi, P, Nahon, J.L, Rostène, W, Parsadaniantz, S. Mélik
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; Behavior, Animal - drug effects; Biochemistry; Biochemistry, Molecular Biology; Biological and medical sciences; Brain Chemistry - drug effects; Cellular biology; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Chemokine CXCL12; Chemokines, CXC - pharmacology; Corpus Striatum - drug effects; CXCR4; Dopamine - metabolism; Dose-Response Relationship, Drug; Functional Laterality; Fundamental and applied biological sciences. Psychology; Isolated neuron and nerve. Neuroglia; Life Sciences; locomotor behavior; Male; microdialysis; Microdialysis - methods; Motor Activity - drug effects; Neurons and Cognition; Neurosciences; Neurotransmitters; patch clamp; Quantitative Methods; Rats; Rats, Wistar; Receptors, CCR4; Receptors, Chemokine - metabolism; Rodents; substantia nigra; Substantia Nigra - drug effects; Tyrosine 3-Monooxygenase - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.04639.x

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.