Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain.
BACKGROUND
Lithium is the most widely prescribed mood stabilizer, but the precise mechanism of lithium is unresolved.


OBJECTIVE
We examine the effects of the administration of therapeutically relevant concentrations of lithium on the expression of brain-derived neurotrophic factor (BDNF) and its receptor, Trk B, as well as glia-derived neurotrophic factor (GDNF) and its receptors, RET and GDNFR-alpha, in the rat brain. In addition, we also examined the effect of another well-prescribed mood stabilizer, valproate, on the expression of BDNF and GDNF.


METHODS
Rats were kept on a 0.2% lithium carbonate-containing diet for 1, 7, 14, or 28 days or treated with valproate (400 mg/kg per day i.p.) for 1 or 14 days. After the brains were rapidly removed, the levels of BDNF, GDNF, and their receptors were measured by ELISA or western blot analysis.


RESULTS
Chronic lithium treatment for 14 and 28 days significantly increased the expression of BDNF in the hippocampus and temporal cortex. In addition, chronic lithium treatment for 14 days significantly increased the expression of BDNF in the frontal cortex. In contrast, acute or chronic dietary lithium treatment did not alter GDNF expression in these brain regions. In addition, acute or chronic lithium treatments did not change the levels of Trk B, RET, or GDNFR-alpha immunoreactivity. As well as lithium, repeated administration of valproate also increased the expression of BDNF in the frontal cortex and hippocampus.


CONCLUSIONS
Our results suggest that the chronic administration of mood stabilizers may produce a neurotrophic effect mediated by the upregulation of BDNF in the rat brain.
Fukumoto
T
T
Department of Psychiatry and Neurosciences, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Morinobu
S
S
Okamoto
Y
Y
Kagaya
A
A
Yamawaki
S
S
D000284:Administration, Oral; D000818:Animals; D018692:Antimanic Agents / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D018021:Lithium Chloride / Q000008:administration & dosage*; D008297:Male; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013702:Temporal Lobe / Q000187:drug effects / Q000378:metabolism
D018692:Antimanic Agents; D019208:Brain-Derived Neurotrophic Factor; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018021:Lithium Chloride