Antidepressant drugs inhibit a glial 5-hydroxytryptamine transporter in rat brain.
We assessed the role of glial cells in the uptake of serotonin (5-hydroxytryptamine, 5-HT). Primary cultures of rat and mouse cortical astrocytes took up and deaminated 5-HT. The antidepressants citalopram, clomipramine, fluoxetine, fluvoxamine, paroxetine and sertraline inhibited this process. The presence of the mRNAs for the 5-HT transporter and monoamine oxidase-A (MOA-A) was established in cultured astrocytes and in adult rat brain areas with (midbrain and brainstem) and without (frontal cortex) serotonergic cell bodies after reverse transcription-polymerase chain reaction and hybridization with probes complementary to the cloned neuronal 5-HT transporter and MAO-A. To examine in vivo the role of astrocytes in the elimination of 5-HT from the extracellular brain space, 5-HT was perfused through dialysis probes implanted in the frontal cortex of conscious rats and its concentration was measured at the probe outlet. Tissue 5-HT recovery was dose-dependently inhibited by the concurrent perfusion of citalopram, fluoxetine and paroxetine, showing that it essentially measured uptake through the high-affinity 5-HT transporter. Rats lesioned with 5,7-dihydroxytryptamine (5,7-DHT; 88% reduction of tissue 5-HT) displayed tissue 5-HT recovery slightly higher than sham-operated rats (55 +/- 2 vs. 46 +/- 3%, P < 0.001), a finding perhaps attributable to the astrogliosis induced by 5,7-DHT denervation. Rats lesioned with 6-hydroxydopamine showed tissue 5-HT uptake similar to controls, suggesting negligible reuptake of 5-HT by catecholaminergic terminals. These results are consistent with the presence of a glial component of 5-HT uptake in the rodent brain, sensitive to antidepressants, which takes place through a 5-HT transporter very similar or identical to that present in neurons.
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Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Cientificas, Spain.
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D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D026901:Membrane Transport Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008995:Monoamine Oxidase / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D014158:Transcription, Genetic
D000928:Antidepressive Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D012701:Serotonin; D008995:Monoamine Oxidase