Prefrontal N-acetylaspartate is strongly associated with memory performance in (abstinent) ecstasy users: preliminary report.

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA or "Ecstasy") is known to damage brain serotonin neurons in animals and possibly humans. Because serotonergic damage may adversely affect memory, we compared verbal memory function between MDMA users and MDMA-na?ve control subjects and evaluated the relationship between verbal memory function and neuronal dysfunction in the MDMA users. METHODS: An auditory verbal memory task (Rey Auditory Verbal Learning Test) was used to study eight abstinent MDMA users and seven control subjects. In addition 1H-MRS was used in different brain regions of all MDMA users to measure N-acetylaspartate/creatine (NAA/Cr) ratios, a marker for neuronal viability. RESULTS: The MDMA users recalled significantly fewer words than control subjects on delayed (p =.03) but not immediate recall (p =.08). In MDMA users, delayed memory function was strongly associated with NAA/Cr only in the prefrontal cortex (R(2) =.76, p =.01). CONCLUSIONS: Greater decrements in memory function predicted lower NAA/Cr levels-and by inference greater neuronal dysfunction-in the prefrontal cortex of MDMA users.     

Validity of [123I]beta-CIT SPECT in detecting MDMA-induced serotonergic neurotoxicity

Recent [123I]beta-CIT single-photon emission computed tomography (SPECT) studies revealed decreased serotonin transporters (SERT) density in the brain of humans with a history of MDMA ("Ecstasy") use. However, [123I]beta-CIT SPECT has until now not been validated as a method for detecting such serotonergic lesions. Therefore, the present study was undertaken. Following baseline [123I]beta-CIT SPECT scans, a rhesus monkey was treated with MDMA (5 mg/kg, s.c. twice daily for 4 consecutive days). SPECT studies 4, 10, and 31 days after MDMA treatment revealed decreases in [123I]beta-CIT binding ratios in the SERT-rich brain region studied (hypothalamic/midbrain region), with SERT density reduced by 39% in this brain region 31 days after treatment. Data obtained with SPECT studies correlated well with SERT density determined with autoradiography after sacrifice of the animal (-34%). In addition, ex vivo [123I]beta-CIT binding studies in rats 1 week after treatment with neurotoxic doses of MDMA (20 mg/kg s.c. twice daily for 4 consecutive days) revealed significant reductions in [123I]beta-CIT binding in SERT-rich regions (including the hypothalamus) when compared to saline-treated rats. The combined results of these studies indicate that SPECT imaging of SERT with [123I]beta-CIT can detect changes in SERT density secondary to MDMA-induced neurotoxicity in the hypothalamic/midbrain region, and possibly other brain regions.     

Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers

Nicotine and other constituents of tobacco smoke elevate dopamine (DA) and serotonin (5-HT) levels in brain and may cause homeostatic adaptations in DA and 5-HT transporters. Since sex steroids alter DA and 5-HT transporter expression, the effects of smoking on DA and 5-HT transporter availability may differ between sexes. In the present study, DA and 5-HT transporter availabilities were quantitated using single photon emission computed tomography (SPECT) imaging approximately 22 h after bolus administration of [123I]beta-CIT, an analog of cocaine which labels DA and 5-HT transporters. Forty-two subjects including 21 pairs of age-, race-, and gender-matched healthy smokers and nonsmokers (12 female and 9 male pairs) were imaged. Regional uptake was assessed by the outcome measures, V3", which is the ratio of specific (i.e., ROI-cerebellar activity) to nondisplaceable (cerebellar) activity, and V3, the ratio of specific to free plasma parent. Overall, striatal and diencephalic [123I]beta-CIT uptake was not altered by smoking, whereas brainstem [123I]beta-CIT uptake was modestly higher (10%) in smokers vs. nonsmokers. When subgrouped by sex, regardless of smoking status, [123I]beta-CIT uptake was higher in the striatum (10%), diencephalon (15%), and brainstem (15%) in females vs. males. The sex*smoking interaction was not significant in the striatum, diencephalon, or brainstem, despite the observation of 20% higher brainstem [123I]beta-CIT uptake in male smokers vs. nonsmokers and less than a 5% difference between female smokers and nonsmokers. The results demonstrate higher DA and 5-HT transporter availability in females vs. males and no overall effect of smoking with the exception of a modest elevation in brainstem 5-HT transporters in male smokers. Although these findings are preliminary and need validation with a more selective 5-HT transporter radiotracer, the results suggest that brainstem 5-HT transporters may be regulated by smoking in a sex-specific manner.     

Comparative in vivo study of iodine-123-labeled beta-CIT and nor-beta-CIT binding to serotonin transporters in rat brain.

Both iodine-123-labeled beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) and nor-beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane) have shown to be suitable radioligands for imaging serotonin (5-HT) transporters. [(123)I]nor-beta-CIT has the highest in vitro affinity for 5-HT transporters among beta-CIT analogs reported so far. However, no direct comparison-studies of these two radiotracers as to their in vivo binding to 5-HT transporters have been reported so far. Therefore, it is still unclear which of the two radiotracers is more suitable for single photon emission computed tomography (SPECT) imaging of 5-HT transporters. The purpose of this study was to compare directly in a controlled design the in vivo [(123)I]beta-CIT and [(123)I]nor-beta-CIT binding to 5-HT transporters under the same conditions in rats with the focus on brain kinetic characteristics by means of a two-compartment analysis. We observed that [(123)I]beta-CIT has a higher binding potential and faster kinetics for 5-HT transporters than [(123)I]nor-beta-CIT, suggesting that [(123)I]beta-CIT may be a more suitable radioligand than [(123)I]nor-beta-CIT for imaging 5-HT transporters with SPECT.     

(+/-)3,4-Methylenedioxymethamphetamine ('Ecstasy')-induced serotonin neurotoxicity: studies in animals

The popular recreational drug, (+/-)3, 4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a potent and selective brain serotonin (5-HT) neurotoxin in animals. MDMA-induced 5-HT neurotoxicity can be demonstrated using a variety of neurochemical, neuroanatomical and, more recently, functional measures of 5-HT neurons. Although the neurotoxic effects of MDMA in animals are widely accepted, the relevance of the animal data to human MDMA users has been questioned, largely because dosages of drugs used in animals are perceived as being much higher than those used by humans. In the present paper, we review the extensive body of data demonstrating that MDMA produced toxic effects on brain 5-HT neurons in animals and present new data indicating that levels of the type 2 vesicular monoamine transporter are reduced in MDMA-treated animals, providing further indication of MDMA's 5-HT neurotoxic potential. Further, we demonstrate, using principles of interspecies scaling, that dosages of MDMA known to be neurotoxic in animals fall squarely in the range of dosages used typically by recreational MDMA users.     

Sustained recreational use of ecstasy is associated with altered pre and postsynaptic markers of serotonin transmission in neocortical areas: a PET study with [11C]DASB and [11C]MDL 100907

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [11C]DASB and the 5-HT(2A) receptor ligand [11C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.     

123I] beta-CIT and single photon emission computed tomography reveal reduced brain serotonin transporter availability in bulimia nervosa.

BACKGROUND: Impaired serotonin transmission has been implicated in the pathophysiology of eating disorders. We investigated the in vivo availability of brain serotonin transporters and dopamine transporters in bulimia nervosa patients. METHODS: Approximately 24 hours after injection of [123I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I] beta-CIT), single photon emission computed tomography scans were performed in 10 medication-free, female bulimic patients and 10 age-matched, healthy females. For quantification of brain serotonin transporter and dopamine transporter availability, a ratio of specific to nonspecific [123I] beta-CIT brain binding was used (V(3)" = target region - cerebellum/cerebellum). RESULTS: Drug-free bulimia nervosa patients showed a 17% reduced brain serotonin transporter availability in the hypothalamus and thalamus, as compared with healthy control subjects (2.4 +/- 0.4 vs. 2.9 +/- 0.4, p =.026), and a similar reduction in striatal dopamine transporter availability. There was a negative correlation of illness duration and serotonin transporter availability (r = -.65; p =.042) and a strong positive correlation between hypothalamic/thalamic and striatal V(3)" (r =.80, p <.001). CONCLUSIONS: This first report of reduced [123I] beta-CIT binding in a relatively small group of patients with bulimia nervosa suggests a reduced hypothalamic and thalamic serotonin transporter availability in bulimia, which is more pronounced with longer duration of illness.     

SPECT measurement of iodine-123-beta-CIT binding to dopamine and serotonin transporters in Parkinson's disease: correlation with symptom severity.

Iodine-123-beta-CIT (2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) binds with high affinity to dopamine (DA) and serotonin (5-HT) transporters. This study examined the correlation of single-photon emission computed tomographic (SPECT) measures of [123I]beta-CIT binding to DA and 5-HT transporters with symptom severity in Parkinson's disease (PD). Forty-six L-dopa-responsive PD patients (Hoehn-Yahr stage 1-3) had SPECT scans at 20-24 h after injection of [123I]beta-CIT. Specific to nondisplaceable uptake ratios (designated V"3) were calculated in the striatum and hypothalamic/midbrain region, where the binding of [123I]beta-CIT is associated primarily with DA and 5-HT transporters, respectively. Striatal V"3 was significantly correlated with Hoehn-Yahr stage and total, motor and activities of daily living scores of Unified Parkinson's Disease Rating Scale (UPDRS). There was a significant correlation between the sum of lateralizing motor UPDRS subscores (tremor, rigidity, bradykinesia) calculated for each side of limbs and V"3 values in the contralateral striatum. No significant correlation was found between striatal V"3 and UPDRS rating of mentation, behavior, and mood. Hypothalamic/midbrain V"3 was not significantly correlated with either Hoehn-Yahr stage or UPDRS scores including both motor and nonmotor measures. The significant correlation of SPECT measures of striatal [123I]beta-CIT binding with motor severity suggests that [123I]beta-CIT binding to striatal DA transporters can serve as an in vivo indicator of disease severity in PD, with potential utility in the serial monitoring of disease progression.     

Experimental studies on 3,4-methylenedioxymethamphetamine (MDMA, “ECSTASY”) and its potential to damage brain serotonin neurons

A number of drugs that fall into the broad category of “ring-substituted amphetamines” have been found to be neurotoxic toward brain monoamine neurons in animals. Several of these drugs, including (3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) and methamphetamine (“speed”) and fenfluramine (“Pondimin”) have been used or abused by humans. A growing body of evidence indicates that humans, like animals, are susceptible to substituted amphetamine-induced neurotoxic injury, and that consequences of this injury can be subtle. This article will review the effects of ring-substituted amphetamine analogs on brain monoamine neurons, using MDMA as the prototype. Studies documenting MDMA neurotoxic potential toward brain serotonin (5-HT) neurons in animals are summarized first. Human MDMA studies are then discussed, beginning with a consideration of methodological challenges in evaluating the status of 5-HT neurons in the living human brain. Recent findings indicating possible functional alterations in brain serotonergic systems in humans with a history of extensive MDMA exposure are then presented, including some new findings on sleep and personality in abstinent MDMA users.     

Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [(123)I]beta-CIT.

BACKGROUND: Several lines of evidence derived from imaging and postmortem studies suggest that schizophrenia is associated with hyperactivity of dopamine function and deficiency in serotonin (5-HT) function. The aim of this study was to investigate potential alterations of striatal dopamine transporters (DAT) and brainstem serotonin transporters (SERT) density in schizophrenia. METHODS: Striatal DAT and brainstem SERT were measured in 24 patients with schizophrenia and 22 matched healthy control subjects using single photon emission computed tomography and [(123)I]beta-CIT. In this cohort of subjects, we previously reported an increase in striatal amphetamine-induced dopamine release, measured as the displacement of the D(2) receptor radiotracer [(123)I]IBZM. RESULTS: No differences were observed between patients and control subjects in the equilibrium uptake ratio (V(3)") of [(123)I]beta-CIT in the striatum, indicating that schizophrenia is not generally associated with an alteration of striatal DAT density; however, a trend level association (p =.07) was observed in patients with schizophrenia between low striatal [(123)I]beta-CIT V(3)" and severity of negative symptoms. After controlling for age, striatal [(123)I]beta-CIT V(3)" in patients was not associated with duration of illness, suggesting that this relative deficit was not secondary to a neurodegenerative process. No correlation was observed between DAT density and amphetamine-induced dopamine release, either in the patients or in the controls. Brainstem [(123)I]beta-CIT V(3)" was unaffected in patients with schizophrenia, and was unrelated to symptomatology. CONCLUSIONS: Schizophrenia is generally not associated with alterations of DAT in the striatum or SERT in the brainstem. In some patients, a relative deficit in dopamine nerve terminals might play a role in the pathophysiology of negative symptoms.     

Sex differences in diencephalon serotonin transporter availability in major depression.

BACKGROUND: Major depression is more prevalent in women than men. The present study evaluated if previous findings that demonstrated decreased 5-hydroxytryptamine (5-HT) transporter availability in depressed patients would be confirmed in a larger sample and also evaluated sex differences. METHODS: Depressed (n = 32) and healthy subjects (n = 32), including 16 pairs of women and men, participated in an iodine-123-2 beta-carbomethoxy-3beta-(4-iodophenyltropane) ([(123)I]beta-CIT) single photon emission computed tomography (SPECT) and a magnetic resonance imaging (MRI) scan. Participants were administered [(123)I]beta-CIT (225.7 +/- 3.7 MBq) and imaged 23.0 +/- 1.6 hours later. Statistical analyses included analysis of variance and a regression analysis of the main and interactive effects of age, sex, and depression. RESULTS: Overall, depressed patients demonstrated 12% lower diencephalon and no change in striatal or brainstem [(123)I]beta-CIT uptake. Significant age by sex, sex by depression, and age by sex by depression interactions were noted due to 22% lower diencephalon [(123)I]beta-CIT uptake in depressed women compared with less than a 1% decrease in depressed men. CONCLUSIONS: As observed previously, diencephalon 5-HT transporter availability is decreased in depressed patients. However, the decrease appears to be sex-specific and age-dependent. These findings suggest that serotonergic mechanisms mediating depressed mood differ between men and women in an age-dependent manner and may explain why young women respond better to treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants.     

Depletion and restoration of endogenous monoamines affects beta-CIT binding to serotonin but not dopamine transporters in non-human primates

The radioligand [123I]beta-CIT binds to dopamine transporters in striatum and to serotonin transporters in brainstem. Endogenous dopamine or serotonin may compete with radioligand binding at monoamine transporters. We used alpha-methyl-p-tyrosine (AMPT) to block dopamine production and measured [123I]beta-CIT binding before and after endogenous dopamine was restored by IV administration of the dopamine precursor L-dihydroxyphenylalanine (L-DOPA) in rhesus monkeys. P-chlorophenylalanine (pCPA) was used to inhibit serotonin production, and [123I]beta-CIT binding was assessed before and after IV administration of the serotonin precursor 5-hydroxy-L-tryptophan (L-5-HTP) restored endogenous serotonin. Pretreatment with benserazide blocked peripheral decarboxylization in both paradigms. Serotonin restoration measurably displaced [123I]beta-CIT binding to brainstem serotonin transporters but not to striatal dopamine transporters. Restoration of dopamine apparently did not affect [123I] beta-CIT binding to striatal dopamine transporters. However, dopamine restoration reduced radioligand binding to brainstem serotonin transporters, most likely due to dopamine release from serotonin neurons following L-DOPA administration. The higher striatal density of dopamine transporters relative to dopamine concentrations may explain why [123I] beta-CIT displacement by endogenous dopamine was not observed. This study indicates that [123I]beta-CIT binding in brainstem (raphe area) is affected by endogenous serotonin release in vivo and that L-DOPA treatment may cause serotonin neurons in the brainstem to corelease dopamine.     

Evidence that both intragastric and subcutaneous administration of methylenedioxymethylamphetamine (MDMA) produce serotonin neurotoxicity in rhesus monkeys

It has been demonstrated that repeated, subcutaneous administration of 3,4-methylenedioxymethamphetamine (MDMA) to rats, guinea pigs, and squirrel monkeys produces long-lasting depletions of serotonin (5-hydroxytryptamine; 5-HT) in several brain regions. Since evidence of degenerating 5-HT neurons has been observed in the rat brain following MDMA injections, it is likely that these depletions are due to neurotoxicity similar to that observed with other substituted amphetamines. The purpose of the present study was to determine if MDMA produces similar evidence of neurotoxicity in rhesus monkeys when administered by either the intragastric (i.g.) or subcutaneous (s.c.) route. Administration of MDMA (5.0 mg/kg/12 h x 4 days) by either i.g. or s.c. routes depleted 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in various brain regions 2 weeks after the last injection. Further, a significant decrease in [3H]5-HT uptake sites in the hippocampus was observed in monkeys treated with MDMA by the i.g. route. Reductions in uptake sites did not achieve statistical significance when drug was administered s.c. The results suggest that repeated administration of MDMA produces long-lasting, potentially neurotoxic effects on central 5-HT neurons in primates and does so when given orally.     

Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder--implications for psychopharmacology.

Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourette's disorder. Striatal D2 and 5-HT1A receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-na?ve or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D2 receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D2 receptor occupancy rates and antipsychotic efficacy has been found. The measurement of 5-HT1A receptors in drug-na?ve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HT1A receptor binding potential in schizophrenia. beta-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age- and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [123I] beta-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the beta-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourette's disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-na?ve TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drug-na?ve TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments.     

(+/-)3,4-Methylenedioxymethamphetamine ('Ecstasy')-induced serotonin neurotoxicity: clinical studies

(+/-)3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') is a brain serotonergic neurotoxin in experimental animals, including nonhuman primates. It is also an increasingly popular recreational drug of abuse, and doses of MDMA that are used recreationally overlap with those that produce serotonin (5-HT) neurotoxicity in animals. Studies in human MDMA users probing for evidence of brain serotonergic neurotoxicity indicate that some MDMA users may incur MDMA-related 5-HT neural injury and, possibly, functional sequelae. In particular, MDMA users have selective decrements in cerebrospinal fluid 5-hydroxyindoleacetic acid and brain 5-HT transporters, similar to nonhuman primates with documented MDMA-induced neurotoxicity. Functional abnormalities seen in MDMA users that may be related to 5- HT injury include cognitive deficits, altered sleep architecture, altered neuroendocrine function, altered behavioral responses to 5-HT selective drugs, and increased impulsivity. Additional studies in animals, as well as longitudinal and epidemiological studies in MDMA users, are required to confirm and extend the present data, and to determine whether MDMA users are at increased risk for developing neuropsychiatric illness as they age.     

Neuroanatomic specificity and time course of alterations in rat brain serotonergic pathways induced by MDMA (3,4-methylenedioxymethamphetamine): assessment using quantitative autoradiography.

The widely abused "designer" drug MDMA (3,4-methylenedioxymethamphetamine) has been shown to cause marked and long-lasting changes in brain serotonergic systems. The present study uses quantitative in vitro autoradiography of 3H-paroxetine labeled 5-HT uptake sites to assess the time-dependent effects of MDMA on 5-HT neurons in specific neuroanatomic loci. Following treatment with MDMA (20 mg/kg, b.i.d. for 4 days), marked decreases in 5-HT uptake sites were observed in a number of brain regions known to receive projections of 5-HT neurons. These regions included cerebral cortex, caudate nucleus, hippocampus, nucleus accumbens, olfactory tubercle, superior and inferior colliculi, geniculate nuclei, and most thalamic nuclei. In contrast, other areas such as the septal nuclei and some thalamic nuclei which also receive 5-HT projections were not substantially affected by this drug. In most regions, decreases in 5-HT uptake sites occurred within 24 hours of the last dose of MDMA and persisted at the 2 week time point. Some regions such as dorsal striatum exhibited a time-dependent reduction with greater reductions occurring at 2 weeks rather than immediately following the MDMA treatment regimen. The density of 5-HT uptake sites in other regions such as endopiriform nucleus and substantia nigra at the 2 week versus 18 hour time point indicated some degree of region-specific recovery. Regions which demonstrated no significant reduction in 5-HT uptake sites included the dorsal and median raphe nuclei, ventral tegmental area, central grey, interpeduncular nucleus, locus coerulus, pontine reticular formation and cerebellum. Likewise, regions containing 5-HT axons of passage (e.g., indusium griseum and lateral hypothalamus) appeared to be insensitive to the neurotoxic effects of MDMA on 5-HT neurons. Furthermore, the neurotoxic effects of MDMA showed specificity in that the catecholamine neurons labeled by 3H-mazindol were unaffected by the treatment regimen. These data indicate that the preferential degeneration of serotonergic neurons by MDMA is mediated primarily at 5-HT terminal regions, whereas regions containing 5-HT perikarya and axons of passage remain relatively unaffected. In addition, the observed time-dependent reductions and recovery of 5-HT uptake sites which were detected within 2 weeks of the treatment regimen in certain brain regions suggest region-specific differences in recovery of 5-HT systems from MDMA-induced lesion.     

Designer drugs: how dangerous are they?

Of the designer drugs, the amphetamine analogues are the most popular and extensively studied, ecstasy (3,4-methylenedioxymethamphetamine; MDMA) in particular. They are used recreationally with increasing popularity despite animal studies showing neurotoxic effects to serotonin (5-HT) and/or dopamine (DA) neurones. However, few detailed assessments of risks of these drugs exist in humans. Previously, there were no methods available for directly evaluating the neurotoxic effects of amphetamine analogues in the living human brain. However, development of in vivo neuroimaging tools have begun to provide insights into the effects of MDMA in human brain. In this review, contributions of brain imaging studies on the potential 5-HT and/or DA neurotoxic effects of amphetamine analogues will be highlighted in order to delineate the risks these drugs engender in humans, focusing on MDMA. An overview will be given of PET, SPECT and MR Spectroscopy studies employed in human users of these drugs. Most of these studies provide suggestive evidence that MDMA is neurotoxic to 5-HT neurones, and (meth)amphetamine to DA neurones in humans. These effects seem to be dose-related, leading to functional impairments such as memory loss, and are reversible in several brain regions. However most studies have had a retrospective design, in which evidence is indirect and differs in the degree to which any causative links can be implied between drug use and neurotoxicity. Therefore, at this moment, it cannot be ascertained that humans are susceptible to MDMA-induced 5-HT injury or (meth)amphetamine-induced DA injury. Finally, although little is known about other amphetamine analogues there are important questions as to the safety of these designer drugs as well, in view of the fact that they are chemically closely related to MDMA and some have been shown to be 5-HT neurotoxins in animals.     

Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users

BACKGROUND: Studies in abstinent methamphetamine (METH) users have demonstrated reductions in brain dopamine transporter (DAT) binding potential (BP), as well as cognitive and motor deficits, but it is not yet clear whether cognitive deficits and brain DAT reductions fully reverse with sustained abstinence, or whether behavioral deficits in METH users are related to dopamine (DA) deficits. This study was conducted to further investigate potential persistent psychomotor deficits secondary to METH abuse, and their relationship to brain DAT availability, as measured using quantitative PET methods with [(11)C]WIN 35428. METHODS: Twenty-two abstinent METH users and 17 healthy non-METH using controls underwent psychometric testing to test the hypothesis that METH users would demonstrate selective deficits in neuropsychiatric domains known to involve DA neurons (e.g., working memory, executive function, motor function). A subset of subjects also underwent PET scanning with [(11)C]WIN 35428. RESULTS: METH users were found to have modest deficits in short-term memory, executive function, and manual dexterity. Exploratory correlational analyses revealed that deficits in memory, but not those in executive or motor function, were associated with decreases in striatal DAT BP. CONCLUSIONS: These results suggest a possible relationship between DAT BP and memory deficits in abstinent METH users, and lend support to the notion that METH produces lasting effects on central DA neurons in humans. As METH can also produce toxic effects on serotonin (5-HT) neurons, further study is needed to address the potential role of brain 5-HT depletion in cognitive deficits in abstinent METH users.     

The neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine on serotonin, dopamine, and GABA-ergic terminals: an in-vitro autoradiographic study in rats

Damage to serotonin (5-HT) terminals following doses of 3,4-methylenedioxymethamphetamine (MDMA) is well documented, and this toxicity is thought to be related to dopamine release that is potentiated by the 5-HT(2A/2C) agonist effects of the drug. Although MDMA and methamphetamine (METH) have some similar dopaminergic activities, they differ in their 5-HT agonistic properties. It is reasoned that the study of the resultant toxicity following equimolar doses of MDMA and METH on both dopamine and 5-HT terminals should offer a comparison of the ability of these drugs to induce neurotoxicity. In order to measure the toxic effects to the brain, rats were given equimolar doses of MDMA (40 mg/kg/day) and METH (32 mg/kg/day) in subcutaneously implanted osmotic minipumps for a period of 5 days, and in-vitro autoradiography using [3H]-paroxetine, [3H]-mazindol, [3H]-methylspiperone, and [3H]-flunitrazepam, was performed on brain sections. The results showed that METH was more toxic to 5-HT terminals than MDMA in forebrain regions, including the anterior cingulate, caudate nucleus, nucleus accumbens, and septum. METH was also more toxic than MDMA to dopamine terminals in the habenula, and posterior retrosplenial cortex. Therefore, we find that METH was more toxic to 5-HT and dopamine terminals in specific brain regions in both pre and post-synaptic sites following continuous equimolar dosing.