Uptake blocker

In addition to halopeiidol, the putative neuroleptics, limcazole (311), lemoxipiide (312), and gevotioline (313) bind to (7-ieceptois as does the dopamine uptake blocker, GBR 12909 (314) and two ligands active at the NMDA receptor, ifenprodil (315) and CNS 1102 (316). NPC 16377, (317) is a selective (7-teceptor ligand. MAO inhibitors and antidepressants also bind to (7-teceptors. Some evidence indicates that (7-teceptors in the brain are in fact a form of cytochrome which may account for the diversity of ligands interacting with (7-sites. 

It was previously demonstrated that amfonelic acid, a DA-uptake blocker, partially prevented the METH-induced decrease in TPH activity (Schmidt et al. 1985). Recently, effects were investigated of a specific DA-uptake blocker, GBR 12909, on the MDMA-induced response in the serotonergic... 

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). 

FIGURE 6. Elution pattern of monoamine uptake blockers and amphetamine analogs from reverse-phase HPLC... 

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... 

Salin-Pascual, R. J. Jimenez-Anguiano, A (1995). Vesamicol, an acetylcholine uptake blocker in presynaptic vesicles, suppresses rapid eye movement (REM) sleep in the rat. Psychopharmacology, fieri. 121, 485-7. 

Ferraro L., Antonelli T., O Connor W. T. el al (1997). Modaflnil an antinarcoleptic drug with a different neurochemical profile to d-amphetamine and dopamine uptake blockers. Biol. Psychiatry 2, 1181-3. 

Figure 7.3 Dose-response effects of MDMA on the release of preloaded [3H]5-HT (left panel) and [3H]DA (right panel) from synaptosomes in vitro. [3H]Transmitter release is expressed as percent of tritium retained in tissue. Various concentrations of MDMA were incubated with or without the 5-HT uptake blocker fluoxetine (10 n/W) in [3H]5-HT assays, whereas various concentrations of MDMA were incubated with or without the DA uptake blocker GBR12909 (10 n/W) in [3H]DA assays. Data are mean SD for three separate experiments, each performed in triplicate. See Baumann et al.39 for methods.

Subjective effects were attenuated by 5-HT uptake blockers, suggesting the involvement of transporter-mediated 5-HT release. 

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. 

Sanderson G, Scholfield CN (1986) Effects of adenosine uptake blockers and adenosine on evoked potentials of guinea-pig olfactory cortex. Pflugers Arch 406(l) 25-30 Sattin A, Rail TW (1970) The effect of adenosine and adenine nucleotides on the cyclic adenosine 3, 5 -phosphate content of guinea pig cerebral cortex slices. Mol Pharmacol 6(1) 13-23 Sawynok J, Zarrindast MR, Reid AR, Doak GJ (1997) Adenosine A3 receptor activation produces nociceptive behaviour and edema by release of histamine and 5-hydroxytryptamine. Eur J Pharmacol 333(1) 1-7... 

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]. 

Fluoxetine represents US know-how at its best and has been aired in the media at a time when biological psychiatry has become supreme in North America. However, we do not know whether the drug is better than earlier antidepressants, whether 5-HT is the main neurotransmitter in depression, and whether the 5-HT uptake blockers have acceptable side effects. 

Kuczenski R, Segal DS (1992) Differential effects of amphetamine and dopamine uptake blockers (cocaine, nomifensine) on caudate and accumbens dialysate dopamine and 3-methoxytyramine. J Pharmacol Exp Ther 262 1085-1094. 

Figure 2.12) turned out to have pronounced antidepressant activity. Imipramine, as well as its metabolite desipramine 44 (Figure 2.12), are neurotransmitter uptake blockers [2, 3]. 

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