Methamphetamine and Methylenedioxymethamphetamine Neurotoxicity: Possible Mechanisms of Cell Destruction

Seiden, Lewis S.; Sabol, Karen E.

doi:10.1037/e495672006-014

Cited by 90 publications

(117 citation statements)

References 8 publications

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“…On the other hand, our results with mCPP do not fit well with the 'free radical' hypothesis often used to explain the toxic effects of amphetamines (Seiden and Sabol 1996;Cadet and Brannock 1998). In this scenario, endogenous 5-HT and DA serve as substrates for the formation of toxic metabolites, such as 5,6-DHT and 6-hydroxydopamine, that generate free radicals and cause cellular damage.…”

Section: Discussioncontrasting

confidence: 98%

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1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

Baumann

Ayestas

Dersch

et al. 2001

Neuropsychopharmacology

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Section: Discussioncontrasting

confidence: 98%

“…For example, there is evidence that drug-induced release of 5-HT can lead to the formation of reactive 5-HT metabolites, such as 5,6-dihydroxytryptamine (5,6-DHT), that cause cellular damage (Commins et al 1987;Seiden and Sabol 1996).…”

mentioning

confidence: 99%

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

Baumann

Ayestas

Dersch

et al. 2001

Neuropsychopharmacology

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“…In addition, tract-tracing studies after MDMA show reduced anterograde [ 3 H]proline transport along ascending 5-HT axonal projections (Callahan et al, 2001). Collectively, these findings have been taken to indicate that MDMA and related drugs have the potential to produce a distal axotomy of brain 5-HT neurons (Battaglia et al, 1987;O'Hearn et al, 1988;Molliver et al, 1990;Fuller, 1992;Wilson et al, 1993;Gibb et al, 1994;Seiden and Sabol, 1996;Green et al, 2003;Gudelsky and Yamamoto, 2003;McCann and Ricaurte, 2004).…”

Section: Introductionmentioning

confidence: 99%

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

Xie

Tong

McLane

et al. 2006

Neuropsychopharmacol

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We studied in vivo expression of the serotonin transporter (SERT) protein after 3,4-methylenedioxymethamphetamine (MDMA), p-chloroamphetamine (PCA), or fenfluramine (FEN) treatments, and compared the effects of substituted amphetamines to those of 5,7-dihydroxytryptamine (5,7-DHT), an established serotonin (5-HT) neurotoxin. All drug treatments produced lasting reductions in 5-HT, 5-HIAA, and [ 3 H]paroxetine binding, but no significant change in the density of a 70 kDa band initially thought to correspond to the SERT protein. Additional Western blot studies, however, showed that the 70 kDa band did not correspond to the SERT protein, and that a diffuse band at 63-68 kDa, one that had the anticipated regional brain distribution of SERT protein (midbrain4 striatum4neocortex4cerebellum), was reduced after 5,7-DHT and was absent in SERT-null animals, was decreased after MDMA, PCA, or FEN treatments. In situ immunocytochemical (ICC) studies with the same two SERT antisera used in Western blot studies showed loss of SERT-immunoreactive (IR) axons after 5,7-DHT and MDMA treatments. In the same animals, tryptophan hydroxylase (TPH)-IR axon density was comparably reduced, indicating that serotonergic deficits after substituted amphetamines differ from those in SERT-null animals, which have normal TPH levels but, in the absence of SERT, develop apparent neuroadaptive changes in 5-HT metabolism. Together, these results suggest that lasting serotonergic deficits after MDMA and related drugs are unlikely to represent neuroadaptive metabolic responses to changes in SERT trafficking, and favor the view that substituted amphetamines have the potential to produce a distal axotomy of brain 5-HT neurons.

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“…Although behavioral consequences associated with long-term METH exposure have been extensively documented in METH abusers (Cretzmeyer et al, 2003;Ling et al, 2006;Meredith et al, 2005), the corresponding magnitude and duration of brain alterations remain unclear due, in part, to the paucity of relevant human data. The framework for postulating METH-associated brain changes in humans has been derived mainly from results of experimental METH studies, predominantly in rodents (Seiden, 1985(Seiden, , 1996Bowyer and Holson, 1995;Davidson et al, 2001;Cadet et al, 2003) and relatively fewer in nonhuman primates (Fischman and Schuster, 1977;Melega et al, 1997;Madden et al, 2005). The extent to which those characterizations can be generalized for interpreting METH's effects on human brain neurochemistry has remained tenuous for many years.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Methamphetamine Administration in the Vervet Monkey Models Aspects of a Human Exposure: Brain Neurotoxicity and Behavioral Profiles

Melega

Jorgensen

Laćan

et al. 2007

Neuropsychopharmacol

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Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys. METH doses were escalated over 33 weeks, with final dosages resulting in estimated peak plasma METH concentrations of 1-3 mM, a range measured in human abusers. With larger METH doses, progressive increases in abnormal behavior and decreases in social behavior were observed on 'injection' days. Anxiety increased on 'no injection' days while aggression decreased throughout the study. Thereafter, during 3 weeks abstinence, differences in baseline vs post-METH behaviors were not observed. Post-mortem analysis of METH brains showed 20% lower striatal DA content while autoradiography studies of precommissural striatum showed 35% lower [ 3 H]WIN35428 binding to the DA transporter. No statistically significant changes were detected for [ 3 H]dihydrotetrabenazine binding to the vesicular monoamine transporter (METH-lower by 10%) or for [ 3 H]SCH 23390 and [ 3 H]raclopride binding to DA D1 and D2 receptors, respectively. Collectively, this long-term, escalating dose METH exposure modeling a human abuse pattern, not associated with high-dose binges, resulted in dose-dependent behavioral effects and caused persistent changes in presynaptic striatal DA system integrity.

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Methamphetamine and Methylenedioxymethamphetamine Neurotoxicity: Possible Mechanisms of Cell Destruction

Cited by 90 publications

References 8 publications

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

1-(m-Chlorophenyl)piperazine (mCPP) Dissociates In Vivo Serotonin Release from Long-Term Serotonin Depletion in Rat Brain

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

Long-Term Methamphetamine Administration in the Vervet Monkey Models Aspects of a Human Exposure: Brain Neurotoxicity and Behavioral Profiles

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