5-HT(1B) receptor-mediated regulation of serotonin clearance in rat hippocampus in vivo.
The 5-hydroxytryptamine (5-HT; serotonin) transporter (5-HTT) is important in terminating serotonergic neurotransmission and is a primary target for many psychotherapeutic drugs. Study of the regulation of 5-HTT activity is therefore important in understanding the control of serotonergic neurotransmission. Using high-speed chronoamperometry, we have demonstrated that local application of 5-HT(1B) antagonists into the CA3 region of the hippocampus prolongs the clearance of 5-HT from extracellular fluid (ECF). In the present study, we demonstrate that the 5-HT(1B) antagonist cyanopindolol does not produce this effect by increasing release of endogenous 5-HT or by directly binding to the 5-HTT. Dose-response studies showed that the potency of cyanopindolol to inhibit clearance of 5-HT was equivalent to that of the selective 5-HT reuptake inhibitor fluvoxamine. Local application of the 5-HT(1A) antagonist WAY 100635 did not alter 5-HT clearance, suggesting that the effect of cyanopindolol to prolong clearance is not via a mechanism involving 5-HT(1A) receptors. Finally, the effect of low doses of cyanopindolol and fluvoxamine to inhibit clearance of 5-HT from ECF was additive. These data are consistent with the hypothesis that activation of terminal 5-HT(1B) autoreceptors increases 5-HTT activity.
Daws
L C
LC
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA. daws@uthscsa.edu
Gould
G G
GG
Teicher
S D
SD
Gerhardt
G A
GA
Frazer
A
A
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004563:Electrochemistry; D005110:Extracellular Space / Q000378:metabolism; D010134:Fenclonine / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008845:Microinjections; D010869:Pindolol / Q000031:analogs & derivatives* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D010134:Fenclonine; D016666:Fluvoxamine; D010869:Pindolol; D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C047975:cyanopindolol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide