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

TY - JOUR

T1 - Genetic variation in 5-hydroxytryptamine transporter expression causes adaptive changes in 5-HT4 receptor levels

AU - Jennings, Katie Ann

AU - Licht, Cecilie Löe

AU - Bruce, Aynsley

AU - Lesch, Klaus-Peter

AU - Knudsen, Gitte Moos

AU - Sharp, Trevor

PY - 2012/9

Y1 - 2012/9

N2 - 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.

AB - 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.

U2 - 10.1017/s1461145711001258

DO - 10.1017/s1461145711001258

M3 - Journal article

C2 - 21846421

SN - 1461-1457

VL - 15

SP - 1099

EP - 1107

JO - International Journal of Neuropsychopharmacology

JF - International Journal of Neuropsychopharmacology

IS - 8

ER -