Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter.
|Title||Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter.|
|Publication Type||Journal Article|
|Year of Publication||2005|
|Authors||Kim, D-K, Tolliver TJ, Huang S-J, Martin BJ, Andrews AM, Wichems C, Holmes A, Lesch K-P, Murphy DL|
|Date Published||2005 Nov|
|Keywords||Animals, Aorta, Blotting, Northern, Brain, Chromatography, High Pressure Liquid, Dopamine, Female, Gene Expression Regulation, Hydroxyindoleacetic Acid, Kidney, Levodopa, Liver, Lung, Male, Methyldopa, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Myocardium, Nonlinear Dynamics, Norethandrolone, Pancreas, RNA, Messenger, Serotonin, Serotonin Plasma Membrane Transport Proteins, Sex Factors, Spleen, Time Factors, Tryptophan Hydroxylase|
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.