RESUMEN
Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the D3 receptor-preferring radioligand [(11)C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n=12) and healthy controls (n=11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54-63% greater [(11)C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by D3 receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, and support the hypothesis that dopaminergic sensitization involving D3-related mechanisms might contribute to the pathophysiology of behavioral addictions.
Asunto(s)
Anfetamina/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dopaminérgicos/farmacología , Dopamina/metabolismo , Juego de Azar/metabolismo , Adulto , Encéfalo/diagnóstico por imagen , Agonistas de Dopamina , Juego de Azar/diagnóstico por imagen , Humanos , Masculino , Modelos Neurológicos , Oxazinas , Tomografía de Emisión de Positrones , Radiofármacos , Receptores de Dopamina D3/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
Evidence that the widely used methamphetamine analog MDMA (3,4-methylenedioxymethamphetamine, ecstasy) might damage brain serotonin neurones in humans is derived from imaging investigations showing variably decreased binding of radioligands to the serotonin transporter (SERT), a marker of serotonin neurones. However, in humans, it is not known whether low SERT binding reflects actual loss of SERT protein itself. As this question can only be answered in post-mortem brain, we measured protein levels of SERT and that of the rate-limiting serotonin-synthesizing enzyme tryptophan hydroxylase (TPH) in autopsied brain of a high-dose MDMA user. As compared with control values, SERT protein levels were markedly (-48% to -58%) reduced in striatum (caudate, putamen) and occipital cortex and less affected (-25%) in frontal and temporal cortices, whereas TPH protein was severely decreased in caudate and putamen (-68% and -95%, respectively). The magnitude of the striatal SERT protein reduction was greater than the SERT binding decrease typically reported in imaging studies. Although acknowledging limitations of a case study, these findings extend imaging data based on SERT binding and suggest that high-dose MDMA exposure could cause loss of two key protein markers of brain serotonin neurones, a finding compatible with either physical damage to serotonin neurones or downregulation of components therein.
Asunto(s)
Encéfalo/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Adulto , Autopsia , Encéfalo/metabolismo , Humanos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Unión Proteica , Serotoninérgicos/toxicidad , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Triptófano Hidroxilasa/efectos de los fármacos , Triptófano Hidroxilasa/metabolismoRESUMEN
Early post-mortem data suggest that damage to brain serotonin neurones might play a role in some features (e.g., depression) of Parkinson's disease (PD). However, it is not known whether such damage is a typical characteristic of living patients with PD or whether the changes are regionally widespread. To address this question we measured, by positron emission tomography imaging, levels of the brain serotonin transporter (SERT), a marker for serotonin neurones, as inferred from binding of [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB), a second generation SERT radioligand, in subcortical and cerebral cortical brain areas of clinically advanced non-depressed (confirmed by structured psychiatric interview) patients with PD. SERT binding levels in PD were lower than those in controls in all examined brain areas, with the changes statistically significant in orbitofrontal cortex (-22%), caudate (-30%), putamen (-26%), and midbrain (-29%). However, only a slight non-significant reduction (-7%) was observed in dorsolateral pre-frontal cortex, an area implicated in major depression. Our imaging data suggests that a modest, regionally widespread loss of brain serotonergic innervation might be a common feature of advanced PD. Further investigation will be required to establish whether SERT binding is more or less decreased in those patients with PD who also have major depressive disorder.
Asunto(s)
Química Encefálica/fisiología , Encéfalo/metabolismo , Enfermedad de Parkinson/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Serotonina/metabolismo , Anciano , Bencilaminas , Unión Competitiva/fisiología , Biomarcadores/análisis , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Radioisótopos de Carbono , Trastorno Depresivo/metabolismo , Trastorno Depresivo/fisiopatología , Regulación hacia Abajo/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/fisiopatología , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Transmisión Sináptica/fisiologíaRESUMEN
Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.
Asunto(s)
Cuerpo Estriado/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Radiofármacos , Sustancia Negra/diagnóstico por imagen , Biomarcadores , Biotransformación , Barrera Hematoencefálica , Radioisótopos de Carbono/farmacocinética , Ensayos Clínicos como Asunto/métodos , Cocaína/análogos & derivados , Cocaína/farmacocinética , Cuerpo Estriado/metabolismo , Dihidroxifenilalanina/análogos & derivados , Dihidroxifenilalanina/farmacocinética , Dopamina/metabolismo , Radioisótopos de Flúor/farmacocinética , Fluorodesoxiglucosa F18/farmacocinética , Predicción , Humanos , Radioisótopos de Yodo/farmacocinética , Neuronas/química , Neuronas/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/terapia , Tomografía de Emisión de Positrones , Pronóstico , Radiofármacos/farmacocinética , Receptores Dopaminérgicos/metabolismo , Sustancia Negra/metabolismo , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacocinética , Tomografía Computarizada de Emisión de Fotón ÚnicoAsunto(s)
Dihidroxifenilalanina/uso terapéutico , Trastornos Distónicos/genética , GTP Ciclohidrolasa/genética , Mutación Missense , Mutación Puntual , Prolactina/sangre , Sustitución de Aminoácidos , Trastornos Distónicos/sangre , Trastornos Distónicos/tratamiento farmacológico , Exones/genética , Femenino , GTP Ciclohidrolasa/deficiencia , Genes Dominantes , Heterocigoto , Humanos , Masculino , LinajeRESUMEN
The novel finding of decreased activity of aconitase, a key Krebs cycle enzyme highly sensitive to oxidative damage, in cybrid cell lines using mitochondrial DNA from patients with progressive supranuclear palsy (PSP) implies an enzyme abnormality in brain. However, the authors found that postmortem brain aconitase activity is normal in PSP. This suggests that patients with PSP do not have systemic aconitase deficiency and that data derived from cybrid cell models of neurodegenerative disorders might not always predict similar changes in human brain.
Asunto(s)
Aconitato Hidratasa/metabolismo , Encéfalo/enzimología , Parálisis Supranuclear Progresiva/enzimología , Anciano , Encéfalo/patología , Humanos , Atrofia de Múltiples Sistemas/enzimología , Atrofia de Múltiples Sistemas/patología , Parálisis Supranuclear Progresiva/patologíaRESUMEN
BACKGROUND: Despite advances in cardiopulmonary resuscitation and the education of its providers, survival remains dismal for cancer patients suffering in-hospital cardiac arrest. In an effort to determine if characteristics of cardiac arrest would represent a useful parameter for prognostication and recommendations regarding the suitability of ongoing resuscitation for various groups, this review was undertaken for patients who experienced in-hospital cardiac arrest. METHODS: A retrospective study of data gathered between January 1993 and December 1997 was undertaken in a 518-bed comprehensive cancer center. The records of 243 inpatients who experienced cardiac arrest and received cardiopulmonary resuscitation were reviewed, and their course observed until hospital discharge or death. RESULTS: Sixteen of 73 patients (22%) who had sudden, unanticipated cardiac arrests survived to be discharged from the hospital; however, none (0 of 171) of the patients who experienced an anticipated cardiac arrest survived (P < 0.001). Logistic regression analysis revealed that anticipated cardiac arrest associated with metabolic derangement was an independent predictor of hospital mortality. CONCLUSIONS: Patients experiencing an anticipated cardiac arrest, the course of which could not be interrupted through aggressive management in an intensive care unit, have an extremely poor prognosis. Ongoing resuscitative measures in these patients need not be routinely provided. The authors suggest an algorithm for resuscitation that evaluates the characteristics of the arrest as a prognostic factor. This algorithm should be implemented once progressive deterioration spirals toward cardiac arrest that cannot be prevented. Such an approach should avoid painful and costly interventions that are futile with the present techniques of cardiopulmonary resuscitation.
Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco/complicaciones , Paro Cardíaco/terapia , Neoplasias/complicaciones , Neoplasias/mortalidad , Algoritmos , Mortalidad Hospitalaria , Humanos , Pacientes Internos , Modelos Logísticos , Inutilidad Médica , Pronóstico , Órdenes de Resucitación , Estudios Retrospectivos , Análisis de Supervivencia , Cuidado TerminalRESUMEN
End-of-life decisions in critically ill patients with cancer are often complex and fraught with emotion. End-of-life care involves a multidisciplinary approach that takes into account the patient and family's desires and the goals of therapy. Decisions regarding the use of life-support technology at the end of life encompass an outcomes and goal-oriented approach. Ethical, medical, legal, and economic issues should be considered in the assessment of life-support technologies and directives for their appropriate use in the ICU.
Asunto(s)
Toma de Decisiones , Neoplasias/terapia , Cuidado Terminal/normas , Ética Clínica , Humanos , Cuidados para Prolongación de la Vida/normasRESUMEN
BACKGROUND: Animal data indicate that chronic exposure to dopaminergic drugs can alter levels of the dopamine transporter (DAT), which is critically involved in regulation of synaptic dopamine levels. DAT changes could influence the response to therapy in PD. METHODS: A randomized, assessor-blinded, placebo-controlled clinical trial was performed in subjects with early PD to determine whether L-dopa or pramipexole might regulate striatal DAT binding as measured by PET with [(11)C]RTI-32. Thirty clinically asymmetrical patients were randomly assigned to receive 6 weeks of L-dopa (300/75 mg/d), pramipexole (1.5 mg/d), or placebo; PET studies were performed before and after treatment. RESULTS: Mean interval change in DAT binding was significantly reduced by 16% to 22% in all striatal regions (caudate, anterior and posterior putamen) of the L-dopa-treated patients, whereas significant changes in the pramipexole-treated patients were limited to the contralateral caudate (-15%), ipsilateral anterior putamen (-14%), and posterior putamen (-20%). In the placebo group there were significant changes in contralateral caudate (-11%) and ipsilateral anterior putamen (-12%). L-dopa and pramipexole produced similar clinical benefit. CONCLUSIONS: Short-term therapy with L-dopa and, to a lesser extent, pramipexole can modestly down-regulate striatal DAT in patients with early PD. Decreased striatal DAT could increase dopaminergic neurotransmission with potential benefit, but might also play a role in the development of dopamine-related response fluctuations in patients with advanced disease. Our data also suggest caution in interpretation of longitudinal imaging studies employing DAT to assess disease progression and the efficacy of neuroprotective agents.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Proteínas Portadoras/metabolismo , Levodopa/administración & dosificación , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Enfermedad de Parkinson/tratamiento farmacológico , Tiazoles/administración & dosificación , Anciano , Benzotiazoles , Química Encefálica/efectos de los fármacos , Radioisótopos de Carbono , Cocaína/análogos & derivados , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Pramipexol , Receptores Dopaminérgicos/metabolismo , Tomografía Computarizada de EmisiónAsunto(s)
Adyuvantes Anestésicos/envenenamiento , Química Encefálica/efectos de los fármacos , Dopamina/metabolismo , Oxibato de Sodio/envenenamiento , Enfermedad Aguda , Adulto , Dopamina/análisis , Femenino , Ácido Homovanílico/análisis , Ácido Homovanílico/metabolismo , Humanos , Masculino , Trastornos Relacionados con Sustancias/metabolismoRESUMEN
Although the cerebral cortical dopamine D(1) receptor is considered to play a role in normal and abnormal brain function, little information is available on its characteristics in human brain. We compared dopamine-stimulated adenylyl cyclase (AC) activity in homogenates of cerebral cortex (frontal, temporal, parietal, occipital and cingulate cortex) of autopsied brain of neurologically normal subjects to that in striatum. Cerebral cortical AC activity was modestly and dose-dependently stimulated by dopamine (maximal 20-30%) with low microM EC50s and such stimulation was inhibited by the selective dopamine D1 receptor antagonist SCH23390. The magnitude of the maximal stimulation by dopamine was similar in autopsied and biopsied cerebral cortex. The extent of maximal stimulation was similar to that in dopamine-rich striatum (caudate, putamen and nucleus accumbens), despite much lower density of dopamine D1 receptors in cerebral cortex vs. striatum. The EC50 for dopamine stimulation in cerebral cortex (approximately 1 microM) was lower than that for caudate and putamen (approximately 3 microM). No detectable dopamine stimulation was observed in cerebellar cortex, thalamus or hippocampus. Dopamine stimulation in both cerebral cortex and striatum was independent of calcium activation. We conclude that dopamine stimulated AC can be measured in cerebral cortex of human brain allowing for the possibility that this process can be examined in human brain disorders in which dopaminergic abnormalities are suspected.
Asunto(s)
Adenilil Ciclasas/metabolismo , Receptores de Dopamina D1/metabolismo , Telencéfalo/enzimología , Autopsia , Calcio/administración & dosificación , HumanosRESUMEN
BACKGROUND: Recommendations on use of neuromuscular blocking agents include using peripheral nerve stimulators to monitor depth of blockade and concomitantly administering sedatives and/or analgesics. OBJECTIVE: To evaluate critical care nurses' practices in administering neuromuscular blocking agents. METHODS: A 16-item survey was mailed to 483 acute care facilities in the United States. Of these, 246 surveys (51%) were returned and analyzed to determine use of neuromuscular blocking agents, peripheral nerve stimulators, sedatives, and analgesics. Logistic regression analysis was used to find independent predictors of use of peripheral nerve stimulators. RESULTS: Seventy-five percent of respondents reported long-term use of neuromuscular blocking agents in critically ill patients. Of those, 63% monitored the level of blockade with peripheral nerve stimulators. Reasons for not using peripheral nerve stimulators included unavailability of equipment (48%), lack of training (36%), and insufficient evidence that peripheral nerve stimulators improve care (23%). Predictors of use of stimulators were facilities with more than 150 beds (P < .001) and administration of neuromuscular blocking agents by continuous infusion (P < .001). Ninety-five percent of respondents reported using concurrent analgesics/sedatives always or most of the time. Facilities with fewer than 10 beds in the intensive care unit used concurrent analgesics/sedatives significantly less often than did facilities with 10 beds or more (90% vs 98%, respectively; P = .03). CONCLUSIONS: Small and large facilities differ in concomitant use of analgesics/sedatives and peripheral nerve stimulators. Education and research are needed to ensure that patients receive adequate monitoring and sedation during administration of neuromuscular blocking agents.
Asunto(s)
Cuidados Críticos , Encuestas de Atención de la Salud , Bloqueantes Neuromusculares/administración & dosificación , Enfermeras y Enfermeros , Monitoreo de Drogas/métodos , Humanos , Modelos Logísticos , Estados UnidosRESUMEN
Despite the increasing incidence of illicit use of gamma-hydroxybutyrate (GHB), little information is available documenting levels of the drug in GHB fatalities. We measured GHB levels in postmortem blood, brain and hair specimens from a suspected overdose case by gas chromatography/mass spectrometry (GC/MS) following solid phase extraction (SPE) and derivatization with bis(trimethyl-silyl) trifluoroacetamide (BSTFA). Examination found 330 microg/mL GHB in femoral blood and 221 ng/mg GHB in frontal cortex brain tissue, values higher than those typically reported in the literature. The hair shaft was negative for GHB whereas the plucked root bulbs with outer root sheath attached (2,221 ng/mg) and root bulbs after washing and removal of the outer root sheath (47 ng/mg) contained the drug. Our results are consistent with an acute single dose of GHB and, as the toxicology screen was negative for other drugs of abuse, emphasize the significant danger of this drug.
Asunto(s)
Anestésicos Intravenosos/sangre , Anestésicos Intravenosos/envenenamiento , Oxibato de Sodio/sangre , Oxibato de Sodio/envenenamiento , Adulto , Química Encefálica , Femenino , Cromatografía de Gases y Espectrometría de Masas , Cabello/química , HumanosRESUMEN
To establish whether chronic opiate exposure might impair brain dopaminergic or serotonergic function in humans, we assessed biochemical indices of monoaminergic neurotransmitter activity and integrity in post mortem striatum of nine chronic heroin users and 14 control subjects. Striatal levels of the vesicular monoamine transporter were normal, suggesting that the density of dopamine nerve terminals is not reduced in heroin users. In nucleus accumbens, levels of tyrosine hydroxylase protein (-25%) and those of the dopamine metabolite homovanillic acid (-33%) were reduced significantly together with a trend for decreased dopamine (-32%) concentration. These changes could reflect either a compensatory downregulation of dopamine biosynthesis in response to prolonged dopaminergic stimulation caused by heroin, or reduced axoplasmic transport of tyrosine hydroxylase. Striatal levels of serotonin were either normal or elevated whereas concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were decreased by 27-38%. Our data suggest that chronic heroin exposure might produce a modest reduction in dopaminergic and serotonergic activity that could affect motivational state and impulse control, respectively.
Asunto(s)
Biomarcadores/análisis , Dopamina/metabolismo , Dependencia de Heroína/metabolismo , Proteínas de Transporte de Membrana , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Proteínas del Tejido Nervioso , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuropéptidos , Serotonina/metabolismo , Adulto , Proteínas Portadoras/metabolismo , Dopa-Decarboxilasa/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Femenino , Dependencia de Heroína/fisiopatología , Ácido Homovanílico/metabolismo , Humanos , Ácido Hidroxiindolacético/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Neostriado/fisiopatología , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Transporte Vesicular de Aminas Biógenas , Proteínas de Transporte Vesicular de MonoaminasRESUMEN
We reported that the activities of phospholipase A2, phosphocholine cytidylyltransferase and phosphoethanolamine cytidylyltransferase, key phospholipid metabolic enzymes, are low in substantia nigra of normal human brain and that this might reduce the ability of nigral neurons to repair damage to cell membranes. To determine whether adaptive changes in nigral phospholipid metabolism can occur in idiopathic Parkinson's disease we compared activities of 11 catabolic and anabolic enzymes in autopsied brain of 10 patients with Parkinson's disease to those in control subjects. Nigral activity of the catabolic enzyme phospholipase A2 was normal in the Parkinson's disease group, whereas that of the biosynthetic enzymes phosphoethanolamine cytidylyltransferase, phosphocholine cytidylyltransferase, and phosphatidylserine synthase were elevated 193, 48 and 38%, respectively, possibly representing a compensatory response to repair membrane phospholipids. Enzyme activities were normal in all other brain areas with the exception of increased (+26%) activity of calcium-stimulated phospholipase A2 in putamen, a change which could be consequent to either decreased dopaminergic striatal input or to a dopamine nerve terminal degenerative process. Our data indicate that the normally low rate of membrane phospholipid synthesis in the substantia nigra, the primary area of neurodegeneration in Parkinson's disease, is increased during the course of the disorder. We suggest that pharmacotherapies which augment this compensatory response might have utility as a treatment for Parkinson's disease.
Asunto(s)
Citidililtransferasa de Colina-Fosfato/metabolismo , Enfermedad de Parkinson/metabolismo , Fosfolipasas A/metabolismo , Fosfolípidos/biosíntesis , Sustancia Negra/enzimología , Anciano , Anciano de 80 o más Años , Membrana Celular/enzimología , Citidina Difosfato Colina/metabolismo , Activación Enzimática/fisiología , Etanolaminas/metabolismo , Femenino , Humanos , Masculino , Estrés Oxidativo/fisiología , Fosfolipasas A2 , Fosforilcolina/metabolismoRESUMEN
We measured levels of methamphetamine and those of its metabolite amphetamine in 15 autopsied brain regions of 14 human methamphetamine users. Only slight regional differences were observed in drug concentrations among the brain areas. Although, some redistribution of the drugs probably occurred postmortem, these data suggest that methamphetamine might not be preferentially retained in dopamine-rich brain areas but is heterogenously distributed in brain of chronic human users of the drug. The possible pharmacological actions of methamphetamine in both dopamine-rich and poor brain areas of chronic drug users need to be considered.
Asunto(s)
Trastornos Relacionados con Anfetaminas/metabolismo , Trastornos Relacionados con Anfetaminas/patología , Anfetamina/análisis , Autopsia/métodos , Química Encefálica , Encéfalo/metabolismo , Metanfetamina/análisis , Metanfetamina/metabolismo , Adulto , Causas de Muerte , Enfermedad Crónica , Femenino , Cabello/química , Humanos , Masculino , Metanfetamina/envenenamiento , Cambios Post Mortem , Distribución TisularRESUMEN
Spastic paraplegia is not widely recognized to occur in dopa-responsive dystonia (DRD). The authors found a compound heterozygote for novel mutations of the human tyrosine hydroxylase (TH) gene (TH). The patient was initially diagnosed as having spastic paraplegia, but responded completely to levodopa therapy. Exercise-induced stiffness in the patient's father, who had a TH deletion, also responded to levodopa. The data expand the clinical spectrum of TH deficiency and suggest that TH mutations may account for some patients with DRD simulating spastic paraplegia.
Asunto(s)
Distonía/tratamiento farmacológico , Paraplejía/etiología , Paraplejía/genética , Tirosina 3-Monooxigenasa/genética , Niño , Humanos , Masculino , Mutación/genéticaRESUMEN
Animal data have long suggested that an adaptive upregulation of nucleus accumbens dopamine D1 receptor function might underlie part of the dependency on drugs of abuse. We measured by quantitative immunoblotting protein levels of dopamine D1 and, for comparison, D2 receptors in brain of chronic users of methamphetamine, cocaine, and heroin. As compared with the controls, brain dopamine D1 receptor concentrations were selectively increased (by 44%) in the nucleus accumbens of the methamphetamine users, whereas a trend was observed in this brain area for reduced protein levels of the dopamine D2 receptor in all three drug groups (-25 to -37%; P < 0.05 for heroin group only). Our data support the hypothesis that aspects of the drug-dependent state in human methamphetamine users might be related to increased dopamine D1 receptor function in limbic brain.
Asunto(s)
Trastornos Relacionados con Anfetaminas/metabolismo , Dopaminérgicos/efectos adversos , Metanfetamina/efectos adversos , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Adulto , Anciano , Western Blotting , Química Encefálica/efectos de los fármacos , Enfermedad Crónica , Clonación Molecular , Trastornos Relacionados con Cocaína/metabolismo , Dependencia de Heroína/metabolismo , Humanos , Enfermedad de Huntington/metabolismo , Masculino , Persona de Mediana Edad , Núcleo Accumbens/química , Núcleo Accumbens/efectos de los fármacos , Putamen/química , Putamen/efectos de los fármacos , Putamen/metabolismo , Receptores de Dopamina D1/análisis , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/análisis , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismoRESUMEN
We measured concentrations of cocaine and its major metabolites (benzoylecgonine, ecgonine methylester, norcocaine, and cocaethylene) in 15 autopsied brain regions of 14 human chronic cocaine users. Only slight differences were observed in concentrations of cocaine and its metabolites amongst the examined brain areas. Although it is likely that some postmortem redistribution of the drug must have occurred, our data are consistent with the possibility that behaviorally relevant doses of cocaine are widely distributed throughout the brain of humans who use the drug on a chronic basis. Consideration should therefore be given to the possible pharmacological and toxicological actions of cocaine in both striatal and extra-striatal brain areas in human users of the drug.
Asunto(s)
Encéfalo/metabolismo , Cocaína/farmacocinética , Inhibidores de Captación de Dopamina/farmacocinética , Adulto , Anciano , Trastornos Relacionados con Cocaína , Femenino , Humanos , Masculino , Distribución TisularRESUMEN
The authors found that striatal levels of serotonin and those of its metabolite 5-hydroxyindoleacetic acid were severely depleted by 50 to 80% in brain of a chronic user of methylenedioxymethamphetamine (MDMA) whereas concentrations of dopamine were within the normal control range. Our data suggest that MDMA exposure in the human can cause decreased tissue stores of serotonin and therefore some of the behavioral effects of this drug of abuse could be caused by massive release and depletion of brain serotonin.