Neuropharmacogenomic insights into the mechanism of action of lithium in non-human primate model

P.V. Choudary1; M. Molnar1; J.Z. Li2; S.J. Evans3; M.P. Vawter4; H. Tomita4; F. Meng3; D. Walsh4, R.M. Myers2; W.E. Bunney4; H. Akil3; S.J. Watson3; E.G. Jones1
IBRO World Congress of Neuroscience. 2007.


Lithium is remarkably efficacious in stabilizing mood in individuals with manic-depressive illness (bipolar affective disorder), but dosing regimen and treatment length are critical to the efficacy. Neurons, and hippocampal slices cultured in the presence of lithium have revealed putative lithium-responsive candidate genes, most notably glycogen synthase kinase 3ß (GSK3B). However, biochemical basis for obligatory requirement of chronic treatment and optimal doses of lithium and their relation to GSK3B remains poorly understood. To investigate this phenomenon, we treated four rhesus macaques with lithium for = 4 months, and assayed postmortem brains for gene expression signatures. We found direct correlation between lithium-treatment and the catalytic as well as biosynthetic activities of GSK3B. We also observed a wide variation among different brain regions in their response to lithium treatment. The findings, shedding new light on the mechanism of action of lithium, can potentially help in improving target-selectivity of mood stabilizers. We thank Xiaohong Fan, Phong Nguyen, Malalai Yusufzai, Sharon Burke, Mary Hoversten for expert help, Manuel Lopez-Figueroa, Terry Speed, Manhong Dai, and Pinglang Wang for discussions, and the NIMH Conte Center (P50MH60398) for support. The authors are members of the Pritzker Neuropsychiatric Disorders Research Consortium, supported by the Pritzker Neuropsychiatric Disorders Research Fund LLC under a shared IP agreement. The findings are a subject of pending patent applications.