Effects of a chronic lithium treatment on cortical serotonin uptake sites and 5-HT1A receptors.
The objectives of this study were to characterize the effects of a chronic lithium (Li+) treatment on serotonin (5-HT) uptake sites and on 5-HT1A receptors, and to determine the eventual reversibility of the treatment. The experiments were carried out with membranes from rat cerebral cortex using 8-hydroxy-2-(propylamino)tetralin, or [3H]8-OH-DPAT, and [3H]citalopram to label 5-HT1A receptors and 5-HT uptake sites, respectively. Endogenous levels of 5-HT and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography in the cingulate cortex. The saturation curves with [3H]8-OH-DPAT were always best fitted a two-site model. After a treatment with Li+ for 28 days, no alterations in the binding parameters of [3H]8-OH-DPAT to the high- and low-affinity binding sites could be documented. However, competition curves with 5-HT to inhibit [3H]8-OH-DPAT binding revealed 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 receptors and their transduction systems. Saturation studies with [3H]citalopram showed an increase (> 40%) in the density of 5-HT uptake sites after chronic Li+, suggesting a more efficient 5-HT uptake process for the treated animals, in accord with clinical observations. Although 5-HT contents in cingulate cortex remained unchanged after the treatment, 5-H[AA 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 monoamine oxidase. All the effects revealed by [3H]8-OH-DPAT and [3H]citalopram were reversed following a recovery period of two days without Li+. Since symptoms of bipolar affective disorders may reappear if the chronic Li+ treatment is interrupted, the reversibility of the observed effects further supports the importance of central 5-HT synaptic transmission in the pathophysiology and treatment of human affective disorders.
Carli
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Centre de Recherche en Sciences Neurologiques, Faculté de Médecine, Université de Montréal, Québec, Canada.
Afkhami-Dastjerdian
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Reader
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D015283:Citalopram / Q000378:metabolism; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism; D014316:Tritium
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D015283:Citalopram; D006897:Hydroxyindoleacetic Acid; D008094:Lithium; D011985:Receptors, Serotonin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium