Genetic variation in 5-hydroxytryptamine transporter expression causes adaptive changes in 5-HT₄ receptor levels.

Journal article

Genetic variation in 5-HT transporter (5-HTT) expression is a key risk factor for psychiatric disorder and has been linked to changes in the expression of certain 5-HT receptor subtypes. This study investigated the effect of variation in 5-HTT expression on 5-HT₄ receptor levels in both 5-HTT knockout (KO) and overexpressing (OE) mice using autoradiography with the selective 5-HT₄ receptor radioligand, [³H]SB207145. Compared to wild-type (5-HTT⁺/⁺) controls, homozygous 5-HTT KO mice (5-HTT⁻/⁻) had reduced 5-HT₄ receptor binding site density in all brain regions examined (35-65% of 5-HTT⁺/⁺). In contrast, the density of 5-HT₄ receptor binding sites was not significantly different between heterozygous 5-HTT KO mice (5-HTT⁻/⁺) and 5-HTT⁺/⁺ mice. The 5-HT synthesis inhibitor p-chlorophenylalanine (250 mg/kg twice daily for 3 d) abolished the difference in 5-HT₄ binding between 5-HTT⁻/⁻ and 5-HTT⁺/⁺ mice in all brain regions. Compared to wild-type (WT) littermate controls, 5-HTT OE mice had increased 5-HT₄ binding density across all brain regions, except amygdala (118-164% of WT) and this difference between genotypes was reduced by the 5-HTT inhibitor, fluoxetine (20 mg/kg twice daily, 3 d). Together, these findings suggest that variation in 5-HTT expression causes adaptive changes in 5-HT₄ receptor levels which are directly linked to alterations in 5-HT availability.

Authors: Jennings, K; Licht, C; Bruce, A; Lesch, K; Knudsen, G

• Publication status: Published
• Journal: international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
• Volume: 15
• Issue: 8
• Pages: 1099-1107
• Publication date: 2012-09-01
• DOI: 10.1017/s1461145711001258
• EISSN: 1469-5111
• ISSN: 1461-1457
• Language: English
• Keywords: Propane; Serotonin Agents; Tritium; Gene Expression Regulation; Mice; Genetic Variation; Mice, Knockout; Piperidines; Animals; Analysis of Variance; Fluoxetine; Serotonin Uptake Inhibitors; Brain; Receptors, Serotonin, 5-HT4; Serotonin Plasma Membrane Transport Proteins; Mice, Inbred C57BL; Dose-Response Relationship, Drug; Autoradiography; Protein Binding