5-HT1B receptor modulation of the serotonin transporter in vivo: studies using KO mice.
The serotonin transporter (SERT) controls the strength and duration of serotonergic neurotransmission by the high-affinity uptake of serotonin (5-HT) from extracellular fluid. SERT is a key target for many psychotherapeutic and abused drugs, therefore understanding how SERT activity and expression are regulated is of fundamental importance. A growing literature suggests that SERT activity is under regulatory control of the 5-HT1B autoreceptor. The present studies made use of mice with a constitutive reduction (5-HT1B+/-) or knockout of 5-HT1B receptors (5-HT1B-/-), as well as mice with a constitutive knockout of SERT (SERT-/-) to further explore the relationship between SERT activity and 5-HT1B receptor expression. High-speed chronoamperometry was used to measure clearance of 5-HT from CA3 region of hippocampus in vivo. Serotonin clearance rate, over a range of 5-HT concentrations, did not differ among 5-HT1B receptor genotypes, nor did [(3)H]cyanoimipramine binding to SERT in this brain region, suggesting that SERT activity is not affected by constitutive reduction or loss of 5-HT1B receptors; alternatively, it might be that other transport mechanisms for 5-HT compensate for loss of 5-HT1B receptors. Consistent with previous reports, we found that the 5-HT1B receptor antagonist, cyanopindolol, inhibited 5-HT clearance in wild-type mice. However, this effect of cyanopindolol was lost in 5-HT1B-/- mice and diminished in 5-HT1B+/- mice, indicating that the 5-HT1B receptor is necessary for cyanopindolol to inhibit 5-HT clearance. Likewise, cyanopindolol was without effect on 5-HT clearance in SERT-/- mice, demonstrating a requirement for the presence of both SERT and 5-HT1B receptors in order for cyanopindolol to inhibit 5-HT clearance in CA3 region of hippocampus. Our findings are consistent with SERT being under the regulatory control of 5-HT1B autoreceptors. Future studies to identify signaling pathways involved may help elucidate novel therapeutic targets for the treatment of psychiatric disorders, particularly those linked to gene variants of the 5-HT1B receptor.
Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7756, San Antonio, TX 78229-3900, USA.
Sylvia
S
Montañez
Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7756, San Antonio, TX 78229-3900, USA.
Jaclyn L
JL
Munn
Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7756, San Antonio, TX 78229-3900, USA.
W Anthony
WA
Owens
Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7756, San Antonio, TX 78229-3900, USA.
Rebecca E
RE
Horton
Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7756, San Antonio, TX 78229-3900, USA; Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7764, San Antonio, TX 78229-3900, USA. Electronic address: daws@uthscsa.edu.
Lynette C
LC
Daws
D000818:Animals; D016666:Fluvoxamine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010869:Pindolol / Q000031:analogs & derivatives / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D016666:Fluvoxamine; D010869:Pindolol; D044302:Receptor, Serotonin, 5-HT1B; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C047975:cyanopindolol
5-HT(1B) receptor; Chronoamperometry; Hippocampus; Serotonin transporter; Uptake