Ifoxetine, a compound with atypical effects on serotonin uptake.

Ifoxetine (CGP 15210 G; (+/-)-bis-[cis-3-hydroxy-4-(2,3-dimethyl-phenoxy)]-piperidine sulfate) prevented the depletion of serotonin (5-HT) induced by H 75/12 and p-chloromethamphetamine in the rat brain, and that caused by endogenously released dopamine after the combined administration of haloperidol and amfonelic acid in the rat striatum. These effects are typically caused by compounds that inhibit 5-HT reuptake. Unexpectedly, ifoxetine only weakly inhibited the uptake of radiolabelled 5-HT into rat brain synaptosomes in vitro or ex vivo, the human thrombocytes in vitro or into rat thrombocytes after pretreatment. The following, among the possible explanations for this apparent discrepancy, were considered and regarded as unlikely: the involvement of an active metabolite; the possibility that ifoxetine accumulates in the brain to an extent sufficient to cause in vivo uptake inhibition; a pharmacokinetic interaction with the depleting agents. The possibility that the depletor tests give false positives was also considered. However, ifoxetine lowered brain 5-hydroxyindoleacetic acid and reduced the accumulation of 5-hydroxytryptophan after central decarboxylase inhibition. This suggests that it also interferes with 5-HT metabolism in the absence of depleting agents, which means that it interacts in some way with serotonergic transmission. Ifoxetine displayed weak or no interactions with 5-HT1, 5-HT2, alpha 1-, alpha 2- and beta-noradrenoceptors, histamine H1, muscarinic acetylcholine, opiate, GABA A, and benzodiazepine receptors in vitro, and with dopamine and 5-HT2 receptors in vivo. It did not antagonize the noradrenaline (NA) depletion induced by H 77/77 in rat brain and only weakly interfered with the uptake of i.v. injected radiolabelled NA into the rat heart. This suggests that its interaction with the 5-HT system is specific. Due to its atypical properties, among which the rather weak potentiation of the neurological effects of 5-hydroxytryptophan is also important, ifoxetine may exhibit a therapeutic and/or side-effect profile which differs from that of classical 5-HT uptake inhibitors.