Lithium modulates tryptophan hydroxylase 2 gene expression and serotonin release in primary cultures of serotonergic raphe neurons.
Lithium salts are mood-stabilizing agents with acute antimanic properties and proven efficacy in the long-term prevention of manic and depressive episodes. Furthermore, lithium augmentation is a well-established strategy to treat depressed patients, which do not respond to antidepressants alone. There is evidence to suggest that these effects of lithium are due to a synergism with central serotonin (5-HT) neurotransmission. In this study, we investigated the effects of lithium chloride (LiCl, 1 mM) on 5-HT uptake and release in primary serotonergic neurons from rat raphe nuclei. Short-term (8 h) and long-term (14 days) treatment with LiCl resulted in a 20% and 23% increase in 5-HT release, but neither influenced 5-HT uptake across the plasma membrane nor vesicular 5-HT uptake. In lithium-treated raphe neurons, the inhibition of 5-HT uptake by fluoxetine was unchanged. Using real-time reverse transcriptase polymerase chain reaction and Western blotting, we examined the effect of lithium on tryptophan hydroxylase 2 (TPH2) expression, the rate-limiting enzyme in brain 5-HT biosynthesis. Short-term lithium treatment resulted in a 45% decrease in tph2 mRNA expression and a 31% reduction of TPH2 protein levels, which was completely compensated after long-term treatment. Our results suggest that lithium can modify tph2 gene expression and 5-HT release in raphe neurons, providing new insight into the serotonergic mechanisms of action of lithium.
Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Kathrin
K
Scheuch
Markus
M
Höltje
Holger
H
Budde
Marion
M
Lautenschlager
Andreas
A
Heinz
Gudrun
G
Ahnert-Hilger
Josef
J
Priller
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005473:Fluoxetine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011903:Raphe Nuclei / Q000166:cytology*; D051381:Rats; D012044:Regression Analysis; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013301:Streptolysins / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D001426:Bacterial Proteins; D005473:Fluoxetine; D007770:L-Lactate Dehydrogenase; D018021:Lithium Chloride; D011188:Potassium; D012333:RNA, Messenger; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013301:Streptolysins; D014316:Tritium; D014365:Tryptophan Hydroxylase; C025964:streptolysin O; C504569:tph2 protein, rat