Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

Xie, Tao; Tong, Liqiong; McLane, Michael; Hatzidimitriou, George; Yuan, Jie; McCann, Una D.; Ricaurte, George A.

doi:10.1038/sj.npp.1301031

Cited by 83 publications

(95 citation statements)

References 56 publications

(74 reference statements)

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“…Wang et al (2004b) have reported that SERT expression remains unchanged two weeks after a multiple-dose regimen of MDMA despite studies that have decreased radioligand binding to SERT. However, these results are contradicted by a recent report of Xie et al (Xie et al, 2006) in which a MDMA-induced reduction in SERT protein expression was demonstrated, suggesting a loss of 5-HT axons. Additionally, studies have indicated a lack of Fluoro-Jade-B positive neurons in the hippocampus and striatum following administration of MDMA, although a limited number of degenerating neurons have been noted in other brain regions (Schmued, 2003).…”

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confidence: 55%

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

et al. 2007

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The present study quantified the cleaved form of the microtubule associated protein tau (cleaved MAP-tau, C-tau), a previously demonstrated marker of CNS toxicity, following the administration of monoamine-depleting regimens of the psychostimulant drugs amphetamine (AMPH), methamphetamine (METH), ±3,4-methylenedioxymethamphetamine (MDMA), or paramethoxyamphetamine (PMA) in an attempt to further characterize psychostimulant-induced toxicity. A dopamine (DA)-depleting regimen of AMPH produced an increase in C-tau immunoreactivity in the striatum, while a DA-and serotonin (5-HT)-depleting regimen of METH produced an increase in the number of C-tau immunoreactive cells in the striatum and CA2/CA3 and dentate gyrus regions of the hippocampus. MDMA and PMA, two psychostimulant drugs that produce selective 5-HT depletion in the striatum, had no effect on C-tau immunoreactivity in the striatum or hippocampus. Furthermore, 5,7-dihydroxytryptamine (5,7-DHT), an established 5-HT selective neurotoxin, did not produce an increase in C-tau immunoreactivity. Dual fluorescent immunocytochemistry with antibodies to GFAP and C-tau indicated that C-tau immunoreactivity was present in astrocytes, not neurons, suggesting that increased C-tau may be an alternative indicator of reactive gliosis. The present results are consistent with previous findings that the DA-depleting psychostimulants AMPH and METH produce reactive gliosis whereas the 5-HT-depleting drugs MDMA and PMA, as well as the known 5-HT selective neurotoxin 5,7-DHT, do not produce an appreciable glial response. Keywords methamphetamine; 3,4-methylenedioxymethamphetamine; amphetamine; paramethoxyamphetamine; 5,7-dihydroxytryptamine; toxicity Methamphetamine (METH) and ±3,4-methylenedioxymethamphetamine (MDMA) are substituted phenylethylamines whose popularity among young adults continues to be a public

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confidence: 55%

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

et al. 2007

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“…Chronic antidepressant treatments can also result in decreased SERT binding, but this reduction is thought to reflect a downregulation of SERT expression (Benmansour Hirano et al, 2005). It is important to acknowledge that debate continues in the literature regarding the interpretation of MDMA-induced changes in SERT (measured by radioligand binding vs immunoblotting (see Wang et al, 2004Wang et al, , 2005Xie et al, 2006)) as well as other putative measures of serotonergic neurotoxicity such as reduced levels of 5-HT and 5-HIAA (O'Callaghan and Miller, 1993). In the present study, the significant difference in SERT binding between the CITAL/SAL and the SAL/SAL animals complicates interpretation of the 10-week neurochemical data.…”

Section: Discussionmentioning

confidence: 99%

“…MDMA reduces brain levels of serotonin (5-HT), the 5-HT metabolite 5-HIAA, and 5-HT transporter (SERT) binding (reviewed in Green et al, 2003). Immunohistochemical studies using antibodies against 5-HT or SERT have also found decreased immunoreactive fiber density in several forebrain areas of animals treated with MDMA (O'Hearn et al, 1988;Wilson et al, 1993;Xie et al, 2006). Taken together, these findings have generally been interpreted to reflect a pruning of serotonergic fibers (sometimes referred to as a distal axotomy) in the affected areas (Green et al, 2003; although also see Wang et al, 2004Wang et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Piper

Fraiman

Owens

et al. 2007

Neuropsychopharmacol

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High or repeated doses of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy') produce long-lasting deficits in several markers of serotonin (5-HT) system integrity and also alter behavioral function. However, it is not yet clear whether MDMA-induced serotonergic neurotoxicity is responsible for these behavioral changes or whether other mechanisms are involved. The present experiment tested the hypothesis that blocking serotonergic neurotoxicity by pretreatment with the selective 5-HT reuptake inhibitor citalopram will also prevent the behavioral and physiological consequences of an MDMA binge administration. Male, SpragueDawley rats (N ¼ 67) received MDMA (4 Â 10 mg/kg) with or without citalopram (10 mg/kg) pretreatment. Core temperature, ejaculatory response, and body weight were monitored during and immediately following drug treatments. A battery of tests assessing motor, cognitive, exploratory, anxiety, and social behaviors was completed during a 10-week period following MDMA administration. Brain tissue was collected at 1 and 10 weeks after drug treatments for measurement of regional 5-HT transporter binding and (for the 1-week samples) 5-HT and 5-HIAA concentrations. Citalopram pretreatment blocked MDMA-related reductions in aggressive and exploratory behavior measured in the social interaction and hole-board tests respectively. Such pretreatment also had the expected protective effect against MDMA-induced 5-HT neurotoxicity at 1 week following the binge. In contrast, citalopram did not prevent most of the acute effects of MDMA (eg hyperthermia and weight loss), nor did it block the decreased motor activity seen in the binge-treated animals 1 day after dosing. These results suggest that some of the behavioral and physiological consequences of a high-dose MDMA regimen in rats are mediated by mechanisms other than the drug's effects on the serotonergic system. Elucidation of these mechanisms requires further study of the influence of MDMA on other neurotransmitter systems.

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“…The hippocampus, striatum, and cortex have intermediate SERT densities (28,29). In the biodistribution studies, the highest ratio of the brain region of interest to the cerebellum was the hypothalamus-to-cerebellum ratio, suggesting that the lig- ands correctly targeted SERT in vivo.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Characterization of a Series of ¹⁸F-Diaryl Sulfides (¹⁸F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter

Wang

Parhi

Oya³

et al. 2009

J Nucl Med

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PET of the serotonin transporter (SERT) in the brain is a useful tool for examining normal physiologic functions as well as disease states involving the serotonergic system. The goal of this study was to further develop and refine a series of 49-fluoroalkoxy-substituted, 18 F-radiolabeled SERT imaging agents. 2-(29-((Dimethylamino)methyl)-49-(4-18 F-fluorobutoxy)phenylthiol)-benzenamine (3) and 2-(29-((dimethylamino)methyl)-49-(5-18 Ffluoropentoxy)phenylthiol)benzenamine (4) were synthesized and evaluated along with 2 previously reported compounds of this series, 2-(29-((dimethylamino)methyl)-49-(2-18 F-fluoroethoxy)-phenylthiol)benzenamine (1) and 2-(29-((dimethylamino)methyl)-49-(3-18 F-fluoropropoxy)phenylthiol)benzenamine (2). Methods: The in vitro binding affinities of compounds 3 and 4 were determined in monoamine transporter-transfected LLC-PK 1 cell homogenates. In vivo localization of the respective 18 F-labeled compounds was evaluated by biodistribution studies in male Sprague-Dawley rats. Compound 3 was selected for further examination by autoradiographic and PET studies in rats. Results: The corresponding mesylate precursors of 3 and 4 were radiolabeled with 18 F within 75-90 min. Radiochemical yield was 6%235%, specific activity was 15-170 GBq/mmol, and radiochemical purity was greater than 97% (end of synthesis). The compounds showed subnanomolar binding affinities for SERT (inhibition constants, 0.51 and 0.76 nM, respectively), had brain uptake at 2 min of 1.25 and 0.68 percentage injected dose per gram, respectively, and possessed high target-to-nontarget (hypothalamus-to-cerebellum) ratios at 120 min after injection (6.51 and 5.70, respectively). Autoradiographic studies of 18 F-3 showed selective localization in SERT-rich brain regions. PET studies of 18 F-3 showed clear localization in the midbrain, thalamus, and striatum. Conclusion: This compound series was found to have potential for producing a suitable 18 F-radiolabeled PET radiotracer for SERT. Compound 4, the pentoxy derivative, had the lowest brain uptake and target-to-nontarget ratio. Compound 3, the butoxy derivative, had a lower target-to-nontarget ratio than compounds 1 (ethoxy derivative) and 2 (propoxy derivative). Compounds 1 and 2 both hold promise as SERT radioimaging agents, but because of cost limitations, only compound 2 will be evaluated in further studies.

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Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

Cited by 83 publications

References 56 publications

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

In Vivo Characterization of a Series of ¹⁸F-Diaryl Sulfides (¹⁸F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter

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Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

Cited by 83 publications

References 56 publications

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

In Vivo Characterization of a Series of 18F-Diaryl Sulfides (18F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter

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In Vivo Characterization of a Series of ¹⁸F-Diaryl Sulfides (¹⁸F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter