Recent work has indicated that lithium (at 1 mM, a concentration that is efficacious in the treatment of manic-depressive disorders) modulates the level of vesicular monoamine transporter 1 (VMAT1) mRNA in PC12 cells as a function of the differentiation status of these cells. To ascertain whether VMAT expression in neurons is sensitive to lithium, in vivo, rats were fed a lithium-supplemented diet for 21 days (which raised serum lithium to 0.98+/-0.1 mM). Northern analysis revealed an overall increase (199+/-27%) of the neuronal VMAT isoform (VMAT2) in rat brain after lithium. However, in situ hybridization analysis revealed regional differences in the effects of lithium. Thus, VMAT2 mRNA increased by 50-100% over control in the raphe nuclei, ventral tegmental area, and substantia nigra of rats fed the lithium diet. Concomitantly, VMAT2 mRNA declined by about 50% in the locus coeruleus. Because VMAT2 is expressed in neurons that are strongly implicated in regulating mood and behavior, these data support the hypothesis that alterations of VMAT2 expression contribute to the therapeutic effects of lithium in psychiatric disorders.