title: 5-HT(1B)  autoreceptor regulation of serotonin transporter activity in synaptosomes.
abstract: Serotonin-1B (5-HT(1B) ) autoreceptors are located in serotonin (5-HT) terminals, along with serotonin transporters (SERT), and play a critical role in autoregulation of serotonergic neurotransmission and are implicated in disorders of serotonergic function, particularly emotional regulation. SERT modulates serotonergic neurotransmission by high-affinity reuptake of 5-HT. Alterations in SERT activity are associated with increased risk for depression and anxiety. Several neurotransmitter receptors are known to regulate SERT K(m) and V(max) , and previous work suggests that 5-HT(1B) autoreceptors may regulate 5-HT reuptake, in addition to modulating 5-HT release and synthesis. We used rotating disk electrode voltammetry to investigate 5-HT(1B) autoreceptor regulation of SERT-mediated 5-HT uptake into synaptosomes. The selective 5-HT(1B) antagonist SB224289 decreased SERT activity in synaptosomes prepared from wild-type but not 5-HT(1B) knockout mice, whereas SERT uptake was enhanced after pretreatment with the selective 5-HT(1B) agonist CP94253. Furthermore, SERT activity varies as a function of 5-HT(1B) receptor expression-specifically, genetic deletion of 5-HT(1B) decreased SERT function, while viral-mediated overexpression of 5-HT(1B) autoreceptors in rat raphe neurons increased SERT activity in rat hippocampal synaptosomes. Considered collectively, these results provide evidence that 5-HT(1B) autoreceptors regulate SERT activity. Because SERT clearance rate varies as a function of 5-HT(1B) autoreceptor expression levels and is modulated by both activation and inhibition of 5-HT(1B) autoreceptors, this dynamic interaction may be an important mechanism of serotonin autoregulation with therapeutic implications.
authors.affiliation: Department of Comparative Medicine and Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, Washington 98195, USA. cehagan@u.washington.edu
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Hagan
authors.forename: Ross A
authors.initials: RA
authors.lastname: McDevitt
authors.forename: Yusha
authors.initials: Y
authors.lastname: Liu
authors.forename: Amy R
authors.initials: AR
authors.lastname: Furay
authors.forename: John F
authors.initials: JF
authors.lastname: Neumaier
mesh_terms: D000818:Animals; D017353:Gene Deletion; D051379:Mice; D010881:Piperidones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D010881:Piperidones; D044302:Receptor, Serotonin, 5-HT1B; C108518:SB 22489G; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D013141:Spiro Compounds