EFFECTS OF A CHRONIC LITHIUM TREATMENT ORE CORTICAL SEROTONIN UPTAKE SITES AND 5-HT1A RECEPTORS

The objectives of this study were to characterize the effects of a chr onic lithium (Li+) treatment on serotonin (5-HT) uptake sites and on 5 -HT1A receptors, and to determine the eventual reversibility of the tr eatment. The experiments were carried out with membranes from rat cere bral cortex using 8-hydroxy-2-(propylamino)tetralin, or [H-3]8-OH-DPAT , and [H-3]citalopram to label 5-HT1A receptors and 5-HT uptake sites, respectively. Endogenous levels of 5-KT and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography in the cingulate cortex. The saturation curves with [H-3]8-OH-DPAT wer e always best fitted a two-site model. After a treatment with Li+ for 28 days, no alterations in the binding parameters of [H-3]8-OH-DPAT to the high- and low-affinity binding sites could be documented. However , competition curves with 5-HT to inhibit [H-3]8-OH-DPAT binding revea led a decreased proportion of sites with high affinity for the agonist , together with an increased density of sites with low affinity for 5- HT, suggesting an alteration in the coupling efficacy between 5-HT1A r eceptors and their transduction systems. Saturation studies with [H-3] citalopram showed an increase (>40%) in the density of 5-HT uptake sit es after chronic Li+, suggesting a more efficient 5-HT uptake process for the treated animals, in accord with clinical observations. Althoug h 5-HT contents in cingulate cortex remained unchanged after the treat ment, 5-HIAA levels decreased (>30%), leading to a diminished (almost 50%) 5-HT turnover; and also reflecting a more efficient uptake in the treated rats, so that less 5-HT could be degraded by extracellular mo noamine oxidase. All the effects revealed by [H-3]8-OH-DPAT and [H-3]c italopram were reversed following a recovery period of two days withou t Li+. Since symptoms of bipolar affective disorders may reappear if t he chronic Li+ treatment is interrupted, the reversibility of the obse rved effects further supports the importance of central 5-HT synaptic transmission in the pathophysiology and treatment of human affective d isorders.