Regulation of central serotonin transporters by chronic lithium: an autoradiographic study

The objectives of this study were to further characterize the effects of a chronic lithium (Li+) treatment on serotonin (5-HT) uptake sites, and to determine the eventual reversibility of the observed effects. Quantitative autoradiography experiments were carried out on sections from rat brain, using [3H]citalopram to label selectively the 5-HT transporters or uptake sites. In these experiments, we were able to saturate the 5-HT transporters using an isotopic dilution of the radioligand. The lowest densities of [3H]citalopram binding were measured in all cortical regions studied, with the highest cortical labelling in the anterior cingulate cortex. The rostral neostriatum presented a moderate density of labelling, with slightly higher levels in its ventral portion. Relatively high densities were measured in the globus pallidus, hippocampus, and hypothalamus. Finally, the highest densities were found in the brain stem. Indeed, the dorsal raphe nuclei as well as the substantia nigra were characterized by very high amounts of [3H]citalopram binding. The chronic administration of Li+ increased the density of 5-HT uptake sites in cortical regions, and significant differences were observed in the frontal, temporal, and entorhinal-piriform cortices, with an elevation, albeit not significant, in the anterior cingulate region. A significant increase was also observed in the lateral hypothalamus. Since the 5-HT uptake sites were studied with saturating concentrations of citalopram, we can propose that this increase in binding densities can be attributed to an increase in the number of 5-HT transporters. Interestingly, the only modifications observed were located in regions containing nerve terminals of 5-HT neurons, while regions with cell bodies remained unaffected. Moreover, these effects were completely reversed following a recovery of 48 h without Li . Also, there were no modifications in the density of 5-HT uptake sites after only 2 days of Li+. These results, suggesting an anatomically heterogenous increase in 5-HT uptake in chronically treated rats, are in accord with clinical observations and previous reports with homogenate binding assays. Finally, the conclusions from this study further support the importance of central 5-HT synaptic transmission in the pathophysiology and treatment of human affective disorders.