Serotonin uptake blockers

Since the neurotoxic effects of drugs such as parachloroamphetamine on serotonin neurons can be prevented by serotonin uptake blockers (Ross 1976 Sanders-Bush and Steranka 1978). the possibility that serotonin uptake carrier protein was likewise involved in the neurotoxic effects of MDMA was investigated. As shown in figure 4, pretreatment of rats with the seleetive serotonin uptake blocker citalopram (10 ml/kg), prior to each injection of 10 mg/kg MDMA, resulted in nearly complete protection against the neurotoxic effects of MDMA. Citalopram-pretreated rats exhibited only a 15 pereent decrease in serotonin uptake sites. No significant alterations in the eontent of serotonin and 5-HIAA were observed following MDMA treatment, in eomparison with 60 to 80 percent reductions in the serotonergie parameters observed in rats treated with an identical dose of MDMA alone. 

The data deseribed above demonstrate that destruction of serotonin axons by MDMA involves the serotonin aetive uptake carrier and that administration of citalopram, a selective serotonin uptake blocker, prior to administration of MDMA, ean prevent the decreases in serotonin markers elicited by MDMA alone. These data are eonsistent with previous reports for other potent serotonin neurotoxins, demonstrating that pretreatment with serotonin uptake blockers can prevent the neurotoxic effects of parachloroamphetamine (Ross 1976 Sanders-Bush and Steranka 1978). Furthermore, it has been shown that MDMA-induced neurotoxicity can be prevented or reversed if a serotonin uptake blocker such as fluoxetine is administered no later than 12 hours after MDMA treatment (Schmidt 1986). 

Hwang, E. C., and Van Woert, M. H. (1980) Acute versus chronic effects of serotonin uptake blockers on potentiation of the "serotonin syndrome." Commun. PsychopharmacoL, 4 161-167. 

Tremaine LM, Joerg FA. 1989. Automated gas chromatography-electron-capture assay for the selective serotonin uptake blocker sertraline. J Chromatogr B 496 423. 

Gorelick DA. Serotonin uptake blockers and the treatment of alcoholism. Recent Dev Aicohoi 1989 7 267-281. 

L-deprenyl (selegiline), a monoamine oxidase B inhibitor, clonidine and guanfacine, a2-adreno-receptor agonists, and levodopa (L-dopa) have been reported to improve cognitive function in some subjects. Zimeldine, citaloprani, and alaproclate — selective serotonin uptake blockers — have no beneficial effects. 

Talopram 45 and citalopram 46 (Fig. 3.11) are closely related analogues, but talo-pram is a norepinephrine uptake blocker with a selectivity factor of about 550 against serotonin uptake inhibition, whereas citalopram is a serotonin uptake blocker, with a selectivity of 3400 against norepinephrine uptake inhibition. A similar selectivity difference is observed for the even more closely related analogues nisoxetine 47 (norepinephrine uptake selectivity ca. 180) and fluoxetine 48 (serotonin uptake selectivity 54) (Fig. 3.11) [42]. 

Clomipramine (Anafranil) Very effective serotonin -uptake blocker. Obsessive compulsive disorder, depression. Very sedating. 

C. Serotonin syndrome (see p 21) is characterized by confusion, hypomania, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, incoordination, and hyperthermia. This reaction may be seen when a patient taking an MAO inhibitor (p 269) ingests a serotonin uptake blocker. Because of the long duration of effects of MAO inhibitors and most of the serotonin uptake blookers, this reaotion can occur up to several days to weeks after either treatment regimen has been discontinued. The syndrome has also been described in patients taking an overdose of an SSRI or combinations of various SSRIs without concomitant MAO inhibitor use. 

In addition to its relatively high affinity at postsynaptic 5-HT receptors, MDMA exhibited high affinity for 5-HT uptake sites and has been shown to increase the release of [ H]5-HT and block [ H]5-HT uptake in vitro. These data suggest that some of the actions of MDMA may be mediated at presynaptic binding sites. With respect to [ H]5-HT release, MDMA has been reported to increase the release of [ H]5-HT from brain synaptosomes (Nichols et al. 1982) and hippocampal slices (Johnson et al. 1986). With respect to uptake blockade, MDMA has been reported to competitively inhibit H-5-HT uptake in vitro (Shulgin 1986). Furthermore, the neurotoxic effects of in vivo administration of MDMA on serotonin terminals can be blocked by concomitant administration of the 5-HT uptake blocker citalo-pram (Battaglia et al. 1988b Schmidt and Taylor 1987). Additional evidence in support of the hypothesis that MDMA produces some of its... 

Tramadol has about one tenth the pain-relieving ability of morphine.53 There are two enantiomers, and both contribute to pain relief, but via different mechanisms. (+)-Tramadol and the metabolite (+)-0-desmethy 1-tramadol, which is referred to as Ml, are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine re uptake.25 This latter action enhances the inhibitory effects on pain transmission in the spinal cord. Because the actions of the two enantiomers are complementary, they are usually supplied as a racemic mixture. However, because it is a serotonin-reuptake blocker, interaction with other medications can lead to the occurrence of serotonin syndrome.54... 

Although pseudoephedrine toxicity was a possible diagnosis, the authors concluded that serotonin syndrome was more likely, from an interaction of pseudoephedrine with fluoxetine. Patients should be warned about the hazards of taking selective serotonin re-uptake blockers and then self-medicating with ephedrine or pseudoephedrine. 

Uptake blocker (Table 12) display a certain degree of structural relatedness to the endogenous neurotransmitter whose transport is inhibited dopamine uptake by the anonaine, cocaine, ibogaine, and salsolinol (see Scheme II) serotonin by 12-hydroxyibogaine, ibogaine, and norharman noradrenaline and adrenaline by cathinone, ephedrine, salsolinol GABA by arecaidine, and guvacine. Reserpine and deserpidine... 

Pharmacology Bupropion is a weak blocker of the neuronal uptake of serotonin and norepinephrine. 

Agents from this class of antidepressants are selective blockers of the re-uptake of serotonin at presynaptic neurones and have little if any effects on muscarinic, histaminergic, adrenergic or serotonergic receptors. They are as effective as the tricyclic antidepressants in the management of depressive disorders, but have less cardiovascular effects. They have less anticholinergic activity and because of their lower risk of cardiotoxicity in overdose they... 

Early studies from the Pfizer laboratories had revealed that compounds from a series of mzn.s-l-amino-4-phenyl-tetralins possessed potent norepinephrine (NE) uptake blocking activity. The activity was highly specific for the (1/ , 4S)-enantiomer and was confined to the trans derivatives. The corresponding (IS, 4/ )-enantiomer was much less active and the diastereomeric cis racemates were inactive at blocking NE uptake. It was subsequently shown that many compounds from the diastereomeric cis senes were unexpectedly potent and selective inhibitors of serotonin (5-HT) uptake, thus differentiating these compounds from the trans compounds. One of these compounds, sertraline (5), was originally discovered as a racemic mixture. Resolution showed that the (+)-enantiomer was several times more selective for 5-HT uptake blocking activity than the (-)-isomer. The (+)-enantiomer was subsequently shown to possess the in vivo behavioral effects expected of a potent and selective 5-HT blocker. Thus, as opposed to... 

MacLeod, S.L. Sudhir, P Wong, C.S., Stereoisomer analysis of wastewater-derived beta-blockers, selective serotonin re-uptake inhibitors, and salbutamol by high-performance liquid chromatography-tandem mass spectrometry J. Chromatogr. A 2007, 1170, 23-33. 

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