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Neurochem Int. 2014 Jul;73:127-31. doi: 10.1016/j.neuint.2013.11.004. Epub 2013 Nov 15.

5-HT1B receptor modulation of the serotonin transporter in vivo: studies using KO mice.

Author information

1
Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7756, San Antonio, TX 78229-3900, USA.
2
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.

Abstract

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.

KEYWORDS:

5-HT(1B) receptor; Chronoamperometry; Hippocampus; Serotonin transporter; Uptake

PMID:
24246466
PMCID:
PMC4224139
DOI:
10.1016/j.neuint.2013.11.004
[Indexed for MEDLINE]
Free PMC Article

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