title: Quantification and pharmacological characterization of dialysate levels of noradrenaline in the striatum of freely-moving rats: release from adrenergic terminals and modulation by alpha2-autoreceptors.
abstract: Information concerning striatal levels of noradrenaline (NA) remains inconsistent. Here we have addressed this issue using a sensitive method of HPLC coupled to amperometric detection. The NA reuptake-inhibitor, reboxetine, selectively elevated levels of NA versus dopamine (DA), and NA levels were also selectively elevated by the alpha2-adrenoceptor (AR) antagonist, atipamezole. The actions of atipamezole were mimicked by the preferential alpha2A-AR antagonist, BRL44408, while JO-1 and prazosin, preferential antagonists at alpha2C-ARs, caused less marked elevations in NA levels. In contrast to antagonists, the alpha2-AR agonist, S18616, decreased NA levels and likewise suppressed those of DA. Unilateral lesions of the substantia nigra with 6-hydroxydopamine depleted DA levels without affecting those of NA. Further, the D3/D2 receptor agonist, quinelorane, decreased levels of DA without modifying those of NA. However, the D3/D2 receptor antagonists, haloperidol and raclopride, and the DA reuptake-inhibitor, GBR12935, elevated levels of both DA and NA. Levels of 5-HT (but not of NA or DA) were increased only by the 5-HT reuptake-inhibitor, citalopram. They were decreased by S18616 and prazosin, reflecting the inhibitory and excitatory influence of alpha2- and alpha1-ARs, respectively, upon serotonergic pathways. In conclusion, NA in the striatum is derived from adrenergic terminals. Its release is subject to tonic, inhibitory control by alpha2-ARs, possibly involving both alpha2A- and alpha2C-AR subtypes, though their respective contribution requires clarification. A role of dopaminergic terminals in the reuptake of NA likely explains the elevation in its levels elicited by DA reuptake-inhibitors and D3/D2 receptor antagonists.
authors.affiliation: Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde, Croissy/Seine 78290, France. alain.gobert@fr.netgrs.com
authors.forename: Alain
authors.initials: A
authors.lastname: Gobert
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Billiras
authors.forename: Laetitia
authors.initials: L
authors.lastname: Cistarelli
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D017660:Autoreceptors; D018341:Receptors, Adrenergic, alpha-2; D011954:Receptors, Dopamine; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine