title: Spatiotemporal interaction of alpha(2) autoreceptors and noradrenaline transporters in the rat locus coeruleus: implications for volume transmission.
abstract: We investigated the roles of alpha(2) autoreceptors and noradrenaline (NA) transporters on NA efflux and uptake in the rat locus coeruleus after electrical stimulation. NA efflux was evoked by various trains (50 pulses, 10-500 Hz) and measured by fast cyclic voltammetry. NA efflux and uptake half-time (t(1/2)) were stimulus-dependent, ranging from 43 +/- 3 nM and 2.45 +/- 0.21 s, respectively, with 500-Hz stimuli to 127 +/- 11 nM and 4.41 +/- 0.34 s, respectively, with 100-Hz trains. Based on these data, we calculate that each transporter removes 0.19 NA molecules from the extracellular space every second, a velocity compatible more with transporter-than channel-mode conduction. Dexmedetomidine (10 nM) decreased NA efflux by approximately 30% on stimulations of < or =1 s in duration. BRL 44408 (1 microM) increased NA efflux on stimuli of > or =2 s (by up to 92 +/- 16%). Desipramine (50 nM) increased NA efflux on stimuli of > or =1 s (by 113 +/- 24%) but slowed NA uptake on all stimuli. When given together, the effects of desipramine and BRL 44408 were additive at stimuli of >or =1 s but showed potentiation on shorter trains. There was a significant time delay for the elevation of NA efflux by blockade of uptake (0.79 s) or autoreceptors (1.14 s), suggesting that both are located extrasynaptically and that NA must diffuse through the extracellular space to these structures. We suggest that released NA may interact with alpha(2) autoreceptors and NA transporters as far as 10 microm from the release sites, an action compatible with a volume transmission role of NA in the locus coeruleus.
authors.affiliation: Neurotransmission Laboratory, Academic Department of Anaesthesia and Intensive Care, St. Bartholomew's and Royal London School of Medicine and Dentistry, Royal London Hospital, London, England.
authors.forename: L F
authors.initials: LF
authors.lastname: Callado
authors.forename: J A
authors.initials: JA
authors.lastname: Stamford
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D020927:Dexmedetomidine / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D008125:Locus Coeruleus / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000493:pharmacokinetics*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D027981:Symporters; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D017660:Autoreceptors; D002352:Carrier Proteins; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018341:Receptors, Adrenergic, alpha-2; C493226:Slc6a2 protein, rat; D027981:Symporters; D020927:Dexmedetomidine; D003891:Desipramine; D009638:Norepinephrine; C072125:BRL 44408