title: 5-HT(1B) receptor regulation of serotonin (5-HT) release by endogenous 5-HT in the substantia nigra.
abstract: Axonal release of serotonin (5-hydroxytryptamine, 5-HT) in the CNS is typically regulated by presynaptic 5-HT autoreceptors. Release of 5-HT in substantia nigra pars reticulata (SNr), a principal output from the basal ganglia, has seemed an interesting exception to this rule. The SNr receives one of the highest densities of 5-HT innervation in mammalian brain and yet negative feedback regulation of axonal 5-HT release by endogenous 5-HT has not been identified here. We explored whether we could identify autoregulation of 5-HT release by 5-HT(1B) receptors in rat SNr slices using fast-scan cyclic voltammetry at carbon-fiber microelectrodes to detect 5-HT release evoked by discrete stimuli (50 Hz, 20 pulses) paired over short intervals (1-10 s) within which any autoreceptor control should occur. Evoked 5-HT release exhibited short-term depression after an initial stimulus that recovered by 10 s. Antagonists for 5-HT(1B) receptors, isamoltane (1 microM) or SB 224-289 (1 microM), did not modify release during a stimulus train, but rather, they modestly relieved depression of subsequent release evoked after a short delay (< or =2 s). Release was not modified by antagonists for GABA (picrotoxin, 100 microM, saclofen, 50 microM) or histamine-H(3) (thioperamide, 10 microM) receptors. These data indicate that 5-HT release can activate a 5-HT(1B)-receptor autoinhibition of subsequent release, which is mediated directly via 5-HT axons and not via GABAergic or histaminergic inputs. These data reveal that 5-HT release in SNr is not devoid of autoreceptor regulation by endogenous 5-HT, but rather is under modest control which only weakly limits 5-HT signaling.
authors.affiliation: University Department of Pharmacology, Oxford, UK. sarah.threlfell@dpag.ox.ac.uk
authors.forename: S
authors.initials: S
authors.lastname: Threlfell
authors.forename: S A
authors.initials: SA
authors.lastname: Greenfield
authors.forename: S J
authors.initials: SJ
authors.lastname: Cragg
mesh_terms: D000818:Animals; D004558:Electric Stimulation; D006632:Histamine / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D013378:Substantia Nigra / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D044302:Receptor, Serotonin, 5-HT1B; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D006632:Histamine