RESUMEN
Mujer de 80 años con síntomas dispépticos a quien se le realizó endoscopia de vías digestivas altas que mostró lesiones polipoides confluentes en la segunda porción del duodeno, cuyo estudio histológico indicó un linfoma no Hodgkin B folicular primario, neoplasia duodenal infrecuente de bajo grado, la cual debe diferenciarse de hiperplasia linfoide folicular reactiva y de otros linfomas
Patient was an 80 year old woman with dyspepsia. An upper endoscopy showed confluent polypoid lesions in the second portion of the duodenum. A histological study showed a follicular B-cell lymphoma. This is a rare low grade neoplasm of duodenum which must be differentiated from follicular reactive hyperplasia and other lymphomas
Asunto(s)
Humanos , Femenino , Anciano de 80 o más Años , Linfoma Folicular , Linfoma no HodgkinRESUMEN
PURPOSE: This study was designed to assess changes in glucose metabolism in rats administered single or repeated doses of MDMA. METHODS: Two different experiments were performed: (1) A single-dose study with four groups receiving 20 mg/kg, 40 mg/kg, saline or heat, and (2) a repeated-dose study with two groups receiving three doses, at intervals of 2 h, of 5 mg/kg or saline. Rats were imaged using a dedicated small-animal PET scanner 1 h after single-dose administration or 7 days after repeated doses. Glucose metabolism was measured in 12 cerebral regions of interest. Rectal temperature and blood glucose were monitored. RESULTS: Peak body temperature was reached 1 h after MDMA administration. Blood glucose levels decreased significantly after MDMA administration. In the single-dose experiment, brain glucose metabolism showed hyperactivation in cerebellum and hypo-activation in the hippocampus, amygdala and auditory cortex. In the repeated-dose experiment, brain glucose metabolism did not show any significant change at day 7. CONCLUSION: These results are the first to indicate that MDMA has the potential to produce significant hypoglycaemia. In addition, they show that MDMA alters glucose metabolism in components of the motor, limbic and somatosensory systems acutely but not on a long-term basis.
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Inhibidores de Captación Adrenérgica/farmacología , Glucemia/metabolismo , Encéfalo/metabolismo , Glucosa/metabolismo , N-Metil-3,4-metilenodioxianfetamina/farmacología , Amígdala del Cerebelo/metabolismo , Animales , Corteza Auditiva/metabolismo , Encéfalo/diagnóstico por imagen , Cerebelo/metabolismo , Femenino , Fluorodesoxiglucosa F18/metabolismo , Hipocampo/metabolismo , Hipoglucemia/metabolismo , Tomografía de Emisión de Positrones/métodos , RatasRESUMEN
AIM: To measure the prevalence of 3,4-methylenedioxymethamphetamine (MDMA) and other drug use in young males entering compulsory military service in Asturias (northern Spain) and to define trends in MDMA use in this group during the period from 1995 to 1999. We also sought to determine whether MDMA users have distinct personality features or higher levels of sensation seeking. METHODS: 3,634 conscripts [mean age (SD) = 20.19 years (2.52)] who entered military service during the period between 1995 and 1999 were evaluated using the World Health Organization (WHO) questionnaire for drug consumption, the Eysenck Personality Questionnaire-A (EPQ-A), and the Zuckerman Sensation Seeking Scale. RESULTS AND CONCLUSIONS: The prevalence of lifetime, previous year and previous month MDMA use among military recruits between 1995 and 1999 was 10.9, 7.8 and 4.5%, ranking fifth among illicit drugs ever used. Once individuals used MDMA for the first time, they were likely to use it again, with 71% of individuals who had ever used MDMA reporting that they had used it during the past year (ranking second only to hallucinogens), and 41% reporting having used it in the last month. Compared to recruits who had never used MDMA (but who may have used other illicit drugs), MDMA users had a more extensive drug abuse history. Recruits who had used MDMA during the year prior to study had significantly higher scores on the Neuroticism and Psychoticism Subscales of the EPQ-A, and reported higher levels of sensation seeking.
Asunto(s)
Alucinógenos , N-Metil-3,4-metilenodioxianfetamina , Trastornos Relacionados con Sustancias/epidemiología , Adulto , Humanos , Estudios Longitudinales , Masculino , Personal Militar , Pruebas de Personalidad , Prevalencia , España/epidemiología , Trastornos Relacionados con Sustancias/psicologíaAsunto(s)
Química Encefálica/efectos de los fármacos , Proteínas Portadoras/análisis , Corteza Cerebral/química , Glicoproteínas de Membrana/análisis , Proteínas de Transporte de Membrana , Trastornos de la Memoria/inducido químicamente , N-Metil-3,4-metilenodioxianfetamina/efectos adversos , Proteínas del Tejido Nervioso , Síndromes de Neurotoxicidad/etiología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/efectos de los fármacos , Cocaína/análogos & derivados , Estudios de Seguimiento , Humanos , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/etiología , Síndromes de Neurotoxicidad/diagnóstico , Síndromes de Neurotoxicidad/diagnóstico por imagen , Pronóstico , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Trastornos Relacionados con Sustancias/complicaciones , Trastornos Relacionados con Sustancias/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único/estadística & datos numéricosRESUMEN
Due to brain tissue heterogeneity, the molecular genetic profile of any neurotransmitter-specific neuronal subtype is unknown. The purpose of this study was to purify a population of dopamine neurons, construct a cDNA library, and generate an initial gene expression profile and a microarray representative of dopamine neuron transcripts. Ventral mesencephalic dopamine neurons were purified by fluorescent-activated cell sorting from embryonic day 13.5 transgenic mice harboring a 4.5-kb rat tyrosine hydroxylase promoter-lacZ fusion. Nine-hundred sixty dopamine neuron cDNA clones were sequenced and arrayed for use in studies of gene expression changes during methamphetamine neurotoxicity. A neurotoxic dose of methamphetamine produced a greater than twofold up-regulation of the mitochondrial cytochrome c oxidase polypeptide I transcript from adult mouse substantia nigra at 12 h posttreatment. This is the first work to describe a gene expression profile for a neuronal subtype and to identify gene expression changes during methamphetamine neurotoxicity.
Asunto(s)
Inhibidores de Captación de Dopamina/toxicidad , Dopamina/análisis , Complejo IV de Transporte de Electrones/biosíntesis , Perfilación de la Expresión Génica , Biblioteca de Genes , Metanfetamina/toxicidad , Proteínas del Tejido Nervioso/biosíntesis , Neuronas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Ácido 3,4-Dihidroxifenilacético/análisis , Animales , ADN Complementario/genética , Complejo IV de Transporte de Electrones/genética , Inducción Enzimática , Femenino , Genes Sintéticos , Operón Lac , Masculino , Mesencéfalo/citología , Mesencéfalo/embriología , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/genética , Regiones Promotoras Genéticas , Ratas , Transcripción Genética , Tirosina 3-Monooxigenasa/genéticaRESUMEN
The present studies examined the role of endogenous dopamine (DA) in methamphetamine (METH)-induced dopaminergic neurotoxicity while controlling for temperature-related neuroprotective effects of the test compounds, reserpine and alpha-methyl-p-tyrosine (AMPT). To determine if the vesicular pool of DA was essential for the expression of METH-induced DA neurotoxicity, reserpine (3 mg/kg, given iintraperitoneally 24-26 h prior to METH) was given prior to a toxic dose regimen of METH. Despite severe striatal DA deficits during the period of METH exposure, mice treated with reserpine prior to METH developed long-term reductions in striatal DA axonal markers, suggesting that vesicular DA stores were not crucial for the development of METH neurotoxicity, but leaving open the possibility that cytoplasmic DA might be involved. To evaluate this possibility, cytoplasmic DA stores were depleted with AMPT prior to METH administration. When this study was carried out at 28 degrees C, complete neuroprotection was observed, likely due to lingering effects on core temperature because when the same study was repeated at 33 degrees C (to eliminate AMPT's hypothermic effect in METH-treated animals), the previously observed neuroprotection was no longer evident. In the third and final set of experiments, mice were pretreated with a combination of reserpine and AMPT, to deplete both vesicular and cytoplasmic DA pools, and to reduce striatal DA levels to negligible values during the period of METH administration (< 0.05%). When core temperature differences were eliminated by raising ambient temperature, METH-induced DA neurotoxic changes were evident in mice pretreated with reserpine and AMPT. Collectively, these findings bring into question the view that endogenous DA plays an essential role in METH-induced DA neurotoxicity.
Asunto(s)
Química Encefálica/fisiología , Inhibidores de Captación de Dopamina/toxicidad , Dopamina/fisiología , Metanfetamina/toxicidad , Síndromes de Neurotoxicidad/patología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Temperatura Corporal/efectos de los fármacos , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Masculino , Ratones , Reserpina/farmacología , Simpaticolíticos/farmacología , alfa-Metiltirosina/farmacologíaRESUMEN
Although the neurotoxic potential of methamphetamine (METH) is well established, underlying mechanisms have yet to be identified. In the present study, we sought to determine whether ionic dysregulation was a feature of METH neurotoxicity. In particular, we reasoned that if METH impairs the function of Na(+)/H(+) and/or Na(+)/Ca(2+) antiporters by compromising the inward Na(+) gradient [via prolonged DA transporter (DAT) activation and Na(+)/K(+) ATPase inhibition], then amiloride (AMIL) and other inhibitors of Na(+)/H(+) and/or Na(+)/Ca(2+) exchange would potentiate METH neurotoxicity. To test this hypothesis, mice were treated with METH alone or in combination with AMIL or one of its analogs; 1 week later, the animals were killed for studies of dopamine (DA) neuronal integrity. AMIL markedly potentiated the toxic effect of METH on DA neurons. Potentiation was not caused by increased core temperature, enhanced DAT activity or higher METH brain levels. The DAT inhibitor, WIN-35,428, protected completely against METH-induced DA neurotoxicity in AMIL pretreated animals, suggesting that the potentiating effects of AMIL require a METH/DAT interaction. Findings with METH and AMIL were extended to six other AMIL analogs (MIA, EIPA, DIMA, BENZ, BEP, DiCBNZ), another species (rats), and neuronal type (5-HT neurons). These results support the notion that ionic dysregulation may play a role in METH neurotoxicity.
Asunto(s)
Inhibidores de Captación de Dopamina/toxicidad , Inhibidores Enzimáticos/toxicidad , Metanfetamina/toxicidad , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Intercambiador de Sodio-Calcio/antagonistas & inhibidores , Intercambiadores de Sodio-Hidrógeno/antagonistas & inhibidores , Amilorida/análogos & derivados , Amilorida/farmacología , Animales , Monoaminas Biogénicas/metabolismo , Temperatura Corporal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Diuréticos/farmacología , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/metabolismo , Masculino , Metanfetamina/metabolismo , Ratones , Ratas , Ratas Sprague-Dawley , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoAsunto(s)
Alucinógenos/efectos adversos , N-Metil-3,4-metilenodioxianfetamina/efectos adversos , Degeneración Nerviosa/inducido químicamente , Serotonina/metabolismo , Animales , Encéfalo/efectos de los fármacos , Ensayos Clínicos como Asunto/normas , Humanos , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , RiesgoRESUMEN
To further evaluate the serotonin (5-HT) neurotoxic potential of substituted amphetamines, we used tritiated proline to examine anterograde transport along ascending axonal projections originating in the rostral raphe nuclei of animals treated 3 weeks previously with (+/-)fenfluramine (FEN, 10 mg/kg, every 2 h x 4 injections; i.p.) or (+/-)3,4-methylenedioxymethamphetamine (MDMA, 20 mg/kg, twice daily for 4 days; s.c.). The documented 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT, 75 microg; ICV; 30 min after pretreatment with pargyline, 50 mg/kg; i.p., and desipramine 25 mg/kg; i.p.), served as a positive control. Along with anterograde axonal transport, we measured two 5-HT axonal markers, 5-HT and 5-hydroxyindoleacetic acid (5-HIAA). Prior treatment with FEN or MDMA led to marked reductions in anterograde transport of labeled material to various forebrain regions known to receive 5-HT innervation. These reductions were associated with lasting decrements in 5-HT axonal markers. In general, decreases in axonal transport were less pronounced than those in 5-HT and 5-HIAA. However, identical changes were observed after 5,7-DHT. These results further indicate that FEN and MDMA, like 5,7-DHT, are 5-HT neurotoxins.
Asunto(s)
Transporte Axonal/efectos de los fármacos , Axones/efectos de los fármacos , Fenfluramina/toxicidad , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Vías Nerviosas/efectos de los fármacos , Núcleos del Rafe/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/toxicidad , Serotoninérgicos/toxicidad , 5,7-Dihidroxitriptamina/farmacología , Inhibidores de Captación Adrenérgica/farmacología , Animales , Transporte Axonal/fisiología , Axones/metabolismo , Desipramina/farmacología , Ácido Hidroxiindolacético/metabolismo , Masculino , Inhibidores de la Monoaminooxidasa/farmacología , Vías Nerviosas/citología , Vías Nerviosas/metabolismo , Neurotoxinas/farmacología , Pargilina/farmacología , Prolina/farmacología , Núcleos del Rafe/citología , Núcleos del Rafe/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Factores de Tiempo , Tritio/farmacologíaRESUMEN
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.
RESUMEN
The anorectic drug phentermine produces dose-related toxic effects on brain dopamine (DA) neurons in animals. Until recently, phentermine was widely used in combination with fenfluramine for purposes of appetite suppression and weight loss. With the recent withdrawal of fenfluramine from the market, many people have begun combining phentermine with fluoxetine, a serotonin reuptake inhibitor which also produces mild anorectic effects. Fluoxetine, in addition to inhibiting serotonin reuptake, inhibits hepatic mixed function oxidase, which plays an important role in the metabolic degradation of amphetamines. The purpose of the present study was to assess the effects of fluoxetine on the anorectic and DA neurotoxic effects of phentermine in mice. Phentermine, in combination with fluoxetine, produced greater reductions in food intake and body weight than phentermine alone. The phentermine/fluoxetine combination also produced greater long-term reductions in brain DA levels than phentermine alone, likely reflecting greater DA neurotoxicity of the drug combination. Brain concentrations of phentermine were also found to be higher in animals pretreated with fluoxetine. These findings indicate that fluoxetine potentiates both the anorectic and DA neurotoxic effects of phentermine, probably by increasing phentermine brain levels. The clinical significance of these findings remains to be ascertained.
Asunto(s)
Anorexia/inducido químicamente , Anorexia/fisiopatología , Depresores del Apetito/farmacología , Antagonistas de Dopamina/farmacología , Fluoxetina/farmacología , Fentermina/farmacología , Animales , Depresores del Apetito/metabolismo , Monoaminas Biogénicas/metabolismo , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Hígado/enzimología , Masculino , Ratones , Oxidorreductasas/antagonistas & inhibidores , Fentermina/metabolismo , Factores de TiempoRESUMEN
Hyperthermia exacerbates and hypothermia attenuates methamphetamine (METH)-induced dopamine (DA) neurotoxicity. The mechanisms underlying these temperature effects are unknown. Given the essential role of the DA transporter (DAT) in the expression of METH-induced DA neurotoxicity, we hypothesized that the effect of temperature on METH-induced DA neurotoxicity is mediated, at least in part, at the level of the DAT. To test this hypothesis, the effects of small, physiologically relevant temperature changes on DAT function were evaluated in two types of cultured neuronal cells: (1) a neuroblastoma cell line stably transfected with human DAT cDNA and (2) rat embryonic mesencephalic primary cells that naturally express the DAT. Temperatures for studies of DAT function were selected based on core temperature measurements in animals exposed to METH under usual ambient (22 degrees C) and hypothermic (6 degrees C) temperature conditions, where METH neurotoxicity was fully expressed and blocked, respectively. DAT function, determined by measuring accumulation of radiolabeled DA and 1-methyl-4-phenylpyridinium (MPP(+)), was found to directly correlate with temperature, with higher levels of substrate uptake at 40 degrees C, intermediate levels at 37 degrees C, and lower levels at 34 degrees C. DAT-mediated accumulation of METH also directly correlated with temperature, with greater accumulation at higher temperatures. These findings indicate that relatively small, physiologically relevant changes in temperature significantly alter DAT function and intracellular METH accumulation, and suggest that the effect of temperature on METH-induced DA neurotoxicity is mediated, at least in part, at the level of the DAT.
Asunto(s)
Temperatura Corporal , Proteínas Portadoras/metabolismo , Líquido Intracelular/metabolismo , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Metanfetamina/metabolismo , Proteínas del Tejido Nervioso , Neuronas/metabolismo , 1-Metil-4-fenilpiridinio/metabolismo , 1-Metil-4-fenilpiridinio/toxicidad , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células Cultivadas , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Masculino , Mesencéfalo/citología , Mesencéfalo/embriología , Mesencéfalo/metabolismo , Metanfetamina/toxicidad , Ratones , Neuroblastoma/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , TemperaturaRESUMEN
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.
Asunto(s)
N-Metil-3,4-metilenodioxianfetamina/toxicidad , Síndromes de Neurotoxicidad/patología , Serotoninérgicos/toxicidad , Animales , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
(+/-)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.
Asunto(s)
Alucinógenos/toxicidad , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Síndromes de Neurotoxicidad/patología , Serotoninérgicos/toxicidad , Serotonina/fisiología , Animales , Humanos , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/psicología , Serotonina/metabolismoRESUMEN
To develop an in vitro model of methamphetamine (METH)-induced dopamine (DA) neurotoxicity, striatal synaptosomes were incubated at 37 degrees C with METH for different periods of time (10-80 min), washed once, then tested for DA transporter function at 37 degrees C. METH produced time- and dose-dependent reductions in the V(max) of DA uptake, without producing any change in K(m). Incubation of synaptosomes with the DA neurotoxins 1-methyl-4-phenyl-pyridinium ion, 6-hydroxydopamine, and amphetamine under similar conditions produced comparable effects. In contrast, incubation with fenfluramine, a serotonin neurotoxin, did not. METH-induced decreases in DA uptake were selective, insofar as striatal glutamate uptake was unaffected. Various DA transporter blockers (cocaine, methylphenidate, and bupropion) afforded complete protection against METH-induced decreases in DA uptake, without producing any effect themselves. METH's effects were also temperature dependent, with greater decreases in DA uptake occurring at higher temperatures. Tests for residual drug revealed small amounts (0.1-0.2 microM) of remaining METH, but kinetic studies indicated that decreases in DA uptake were not likely to be due to METH acting as a competitive inhibitor of DA uptake. Decreases in the V(max) of DA uptake were not accompanied by decreases in B(max) of [(3)H]WIN 35,428 binding, possibly because there is no mechanism for removing damaged DA nerve endings from the in vitro preparation Collectively, these results give good support to the development of a valid in vitro model that may prove helpful for elucidating the mechanisms underlying METH-induced DA neurotoxicity.
Asunto(s)
Inhibidores de Captación de Dopamina/toxicidad , Dopamina/fisiología , Metanfetamina/toxicidad , Neostriado/metabolismo , Terminales Presinápticos/fisiología , Animales , Cocaína/análogos & derivados , Cocaína/metabolismo , Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/análisis , Inhibidores de Captación de Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Fenfluramina/farmacología , Ácido Glutámico/metabolismo , Técnicas In Vitro , Cinética , Masculino , Metanfetamina/análisis , Metanfetamina/metabolismo , Neostriado/citología , Neostriado/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Temperatura , Factores de TiempoRESUMEN
The recreational drug, (+/-)3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'), is a potent serotonin (5-HT) neurotoxin in animals. Whether humans who use MDMA incur 5-HT neural injury is unknown. The present studies utilized positron emission tomography (PET) in conjunction with the 5-HT transporter ligand, [11C]McN-5652 to assess the status of brain 5-HT neurons in human MDMA users. Like nonhuman primates treated with neurotoxic doses of MDMA, humans with a history of MDMA use showed lasting decrements in global brain [11C]McN-5652 binding, with decreases in [11C]McN-5652 binding positively correlated to the extent of previous MDMA use. These results suggest that human MDMA use results in brain 5-HT neurotoxicity.
Asunto(s)
Encéfalo/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Serotoninérgicos/farmacología , Animales , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Isoquinolinas/metabolismo , Masculino , N-Metil-3,4-metilenodioxianfetamina/sangre , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Neuronas/efectos de los fármacos , Papio , Serotoninérgicos/sangre , Serotoninérgicos/toxicidad , Antagonistas de la Serotonina/metabolismo , Tomografía Computarizada de EmisiónRESUMEN
Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF(+/-) mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF(+/-) mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF(+/-) mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF(+/-) mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.
Asunto(s)
Agresión , Factor Neurotrófico Derivado del Encéfalo/deficiencia , Encéfalo/fisiopatología , Hiperfagia , Serotonina/metabolismo , Animales , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/genética , Dexfenfluramina/farmacología , Femenino , Heterocigoto , Masculino , Ratones , Ratones Mutantes , Proteínas Proto-Oncogénicas c-fos/biosíntesisRESUMEN
RATIONALE: (+/-) 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a popular drug of abuse and a brain serotonin neurotoxin in animals. Growing evidence indicates that humans are also susceptible to MDMA's neurotoxic effects, although few functional consequences of MDMA-induced 5-HT damage have been identified. OBJECTIVE: The present study sought to determine whether possible differences between MDMA users and control subjects could be unmasked by utilizing a pharmacological challenge with the mixed 5-HT agonist, meta-chlorophenylpiperazine (m-CPP). It was postulated that 5-HT neurotoxicity in MDMA users would be associated with altered 5-HT responsivity, exemplified by altered physiological and behavioral responses to m-CPP. METHODS: Twenty-five MDMA users who had not taken MDMA for at least 3 weeks and 25 controls received intravenous placebo (normal saline) and m-CPP (0.08 mg/kg) in a fixed order, single blind design. Repeated measures of mood, physical symptoms, and blood samples for neuroendocrine analyses were collected during the 90 min after each infusion. RESULTS: MDMA users reported more positive and fewer negative emotions and physical symptoms following m-CPP than controls, and were significantly less likely to report an m-CPP-induced panic attack. Male MDMA users had diminished cortisol and prolactin responses to m-CPP. CONCLUSIONS: The present data indicate that MDMA users have alterations in 5-HT neuronal function, possibly as a consequence of MDMA-induced brain serotonin neural injury.
Asunto(s)
Conducta/efectos de los fármacos , Alucinógenos/efectos adversos , N-Metil-3,4-metilenodioxianfetamina/efectos adversos , Sistemas Neurosecretores/efectos de los fármacos , Piperazinas , Agonistas de Receptores de Serotonina , Serotonina/fisiología , Adulto , Afecto/efectos de los fármacos , Ansiedad/psicología , Femenino , Humanos , Hidrocortisona/sangre , Masculino , Piperazinas/sangre , Prolactina/sangre , Agonistas de Receptores de Serotonina/sangre , Método Simple CiegoRESUMEN
The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](-)McN5652. The impulse response function was calculated by deconvolution analysis of regional time-activity curves, and its peak value (f(max)), its retention value at 75 minutes (fT), and its normalized retention (f(rel) = fT/f(max)) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DV(T)) and its specific binding component (DV(S)). Both the noncompartmental (fT,f(rel)) and the compartmental parameters (DV) were investigated with and without correction for nonspecific binding by simple subtraction of the corresponding value obtained with [11C](-)McN5652. The impulse response function obtained by deconvolution analysis demonstrated high tracer extraction followed by a slow decline in the form of a monoexponential function. Statistical analysis revealed that the best compartmental model in terms of analysis of variance F and condition number of the parameter variance-covariance matrix was the one that was based on a single tissue compartment with parameters k1 and k2 and that also included the parameter of regional cerebral blood volume (BV). The parameter f(rel) demonstrated low between-subject variance (coefficient of variation [CV] = 19%), a midbrain to cerebellum ratio of 1.85, and high correlation with the known density of SERT (r = 0.787 where r is the coefficient of linear correlation between the parameter and the known density of SERT). After correction for nonspecific binding, f(rel) demonstrated further improvement in correlation (r = 0.814) and midbrain to cerebellum ratio (3.09). The variance of the distribution volumes was acceptable when the logarithmic transform lnDV was used instead of DV (17% for the three-parameter model), but correlation of this compartmental parameter was slightly less (r = 0.652 for the three-parameter model) than the correlation of the noncompartmental f(rel) with the known density of SERT, and the midbrain to cerebellum ratio was only 1.5 (uncorrected) and 1.8 (corrected). At the expense of increasing variance, the correlation was increased after correction for nonspecific binding using the inactive enantiomer (r = 0.694; CV = 22%). These results indicate that the kinetics of [11C](+)McN5652 can best be described by a one-tissue compartment model with three parameters (k1, k2, and BV), and that both the noncompartmental parameter f(rel) and the compartmental distribution volumes have the potential for quantitative estimation of the density of SERT. Further validation of the radioligand in experimental and clinical situations is warranted.