Effects of monoamine uptake inhibitors on extracellular and platelet 5‐hydroxytryptamine in rat blood: different effects of clomipramine and fluoxetine

Abstract

The concentration of 5‐hydroxytryptamine (5‐HT) in rat platelet‐free plasma increased significantly 30 min after a single i.p. injection (10 mg kg−1) of each of six inhibitors of the high‐affinity 5‐HT uptake (fluvoxamine, fluoxetine, alaproclate, paroxetine, sertraline and clomipramine). The increases ranged from 226% to 776% of control values. In contrast, imipramine, desipramine and femoxetine had no significant effect. The increase elicited by paroxetine was dependent on the dose (1, 5 and 10 mg kg−1) and returned to control values after 4 h. That observed after clomipramine was also transient and paralleled the plasma concentration of the drug (Spearman‐rank correlation r = 0.43). In vivo, the rat pulmonary vascular endothelium removed trace amounts (8.8 nmol in a bolus) of intravenously injected [14C]‐5‐HT. Paroxetine pretreatment (10 mg kg−1, 30 min before‐hand) reduced this uptake by 73%. Repeated fluoxetine treatments reduced rat whole blood 5‐HT concentration (ca. − 60% after daily 2× 5 mg kg−1, i.p. during 14 days). However, plasma (extracellular) 5‐HT was not increased. Various repeated treatments with clomipramine (i.p. injections or osmotic minipumps, up to 30 mg kg−1 day−1), failed to decrease rat whole blood 5‐HT concentrations. Platelet‐free plasma 5‐HT was also unchanged, even after treatments yielding plasma clomipramine levels 2.7 times higher than those that increased it acutely. These results indicate that the extracellular pool of 5‐HT in rat blood (measured in the platelet‐free plasma) is physiologically under the control of high‐affinity 5‐HT uptake systems. The sustained 5‐HT uptake inhibition does not result in an increase of 5‐HT in platelet‐free plasma, suggesting that adaptative mechanisms are triggered. The distinct long‐term effects of the two antidepressants clomipramine and fluoxetine on rat whole blood 5‐HT suggest a differential in vivo action on the rat 5‐HT uptake.

Study on anti-inflammatory and immunomodulatory effects of fluoxetine in rat models of inflammation

“…37 The effect of this antidepressant on serum TNF-α in this case cannot be explained by its serotonergic mechanism of action. In vitro studies show that fluoxetine inhibits the production of TNF-α in microglial cell cultures.…”

“…Fluoxetine inhibits peripheral serotonin transporters and increases plasma serotonin levels in acutely treated rats. 37 5-HT 4 and 5-HT 7 serotonin receptors are expressed on monocytes and their stimulation reduces secretion of LPS-induced release of TNF-α. 38 In experiments with mice, serotonin also increases the serum levels of IL-10.…”

Blockage of Mouse Muscle Nicotinic Receptors by Serotonergic Compounds

“…Although, further investigations are necessary to determine, at a molecular level, the interaction between serotonergic agents and nicotinic receptors; the modulatory effects of 5_HT and other serotonergic agents on AChRs may be important during stress, in which this amine may reach high levels in the plasma (Sharma et al 1992) and during the administration of antidepressant drugs (Ortiz & Artigas, 1992). Interestingly, fluoxetine (Prozac, an antidepressant used extensively) which has been reported to be a highly selective inhibitor of the 5_HT uptake system, also inhibits muscle and neuronal AChRs (Garc úa-Colunga et al 1997a), as well as 5_HT2C receptors (Ni & Miledi, 1997).…”

Anti-emetic Effect of Mosapride Citrate Hydrate, a 5-HT4 Receptor Agonist, on Selective Serotonin Reuptake Inhibitors (SSRIs)-Induced Emesis in Experimental Animals

“…Inhibition of neuronal 5-HT uptake is the main mechanism of action of numerous antidepressant drugs such as fluoxetine, fluvoxamine, paroxetine, sertraline, and others (2). While these SSRIs have been found to be clinically effective, their beneficial action is occasionally associated with nausea and emesis, which limits their use or prompt the discontinuation of these drugs (3).…”