Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter.
To evaluate the consequences of inactivation of the serotonin transporter (SERT) gene on 5-HT homeostasis and function, 5-HT synthesis and turnover rates were measured using the decarboxylase inhibition method in multiple brain regions (frontal cortex, striatum, brainstem, hippocampus and hypothalamus) from mice with a genetic disruption of SERT. 5-HT synthesis rates were increased 30-60% in the different brain regions of SERT -/- mice compared to littermate +/+ control mice despite 55-70% reductions in tissue 5-HT concentrations. Brain regions that possessed a greater capacity to increase synthesis and turnover (frontal cortex, striatum) demonstrated lesser reductions in tissue 5-HT. Female SERT -/- mice had greater increases (79%) in brain 5-HT synthesis than male -/- mice did (25%), a finding associated with higher brain tryptophan concentrations in females. Despite increased 5-HT synthesis, there was no change in either TPH2 or TPH1 mRNA levels or in maximal in vitro TPH activity in the brainstem of SERT -/- mice. Catecholamine homeostasis as reflected in brain tissue concentrations and in synthesis and turnover of dopamine and norepinephrine was unchanged in SERT -/- mice. Taken together, the results demonstrate a markedly altered homeostatic situation in SERT -/- mice that lack 5-HT reuptake, resulting in markedly depleted tissue stores that are inadequately compensated for by increased 5-HT synthesis, with brain region and gender specificity observed.
Kim
Dong-Kyu
DK
Laboratory of Clinical Science, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.
Tolliver
Teresa J
TJ
Huang
Su-Jan
SJ
Martin
Bradley J
BJ
Andrews
Anne M
AM
Wichems
Christine
C
Holmes
Andrew
A
Lesch
Klaus-Peter
KP
Murphy
Dennis L
DL
D000818:Animals; D001011:Aorta / Q000378:metabolism; D015152:Blotting, Northern / Q000379:methods; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008750:Methyldopa / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D017711:Nonlinear Dynamics; D009639:Norethandrolone / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000502:physiology; D012737:Sex Factors; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D007980:Levodopa; D006897:Hydroxyindoleacetic Acid; D008750:Methyldopa; C019494:alpha-monofluoromethyldopa; C487801:Tph1 protein, mouse; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D009639:Norethandrolone; D004298:Dopamine