RESUMO
Basic studies exploring the importance of the cyclic adenosine monophosphate (cAMP) cascade in major depressive disorder (MDD) have noted that the cAMP cascade is downregulated in MDD and upregulated by antidepressant treatment. We investigated cAMP cascade activity by using 11C-(R)-rolipram to image phosphodiesterase-4 (PDE4) in unmedicated MDD patients and after ~8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). 11C-(R)-rolipram positron emission tomographic (PET) scans were performed in 44 unmedicated patients during a major depressive episode and 35 healthy controls. Twenty-three of the 44 patients had a follow-up 11C-(R)-rolipram PET scan ~8 weeks after treatment with an SSRI. Patients were moderately depressed (Montgomery-Åsberg Depression Rating Scale=30±6) and about half were treatment naïve. 11C-(R)-rolipram binding was measured using arterial sampling to correct for individual differences in radioligand metabolism. We found in unmedicated MDD patients widespread, ~20% reductions in 11C-(R)-rolipram binding compared with controls (P=0.001). SSRI treatment significantly increased rolipram binding (12%, P<0.001), with significantly greater increases observed in older patients (P<0.001). Rolipram binding did not correlate with severity of baseline symptoms, and increased rolipram binding during treatment did not correlate with symptom improvement. In brief, consistent with the results of basic studies, PDE4 was decreased in unmedicated MDD patients and increased after SSRI treatment. The lack of correlation between PDE4 binding and depressive symptoms could reflect the heterogeneity of the disease and/or the heterogeneity of the target, given that PDE4 has four subtypes. These results suggest that PDE4 inhibitors, which increase cAMP cascade activity, may have antidepressant effects.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , AMP Cíclico/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Adulto , Antidepressivos/uso terapêutico , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Estudos de Casos e Controles , Depressão/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 4/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Rolipram/farmacocinética , Transdução de Sinais/efeitos dos fármacosRESUMO
Brain cannabinoid CB1 receptors contribute to alcohol-related behaviors in experimental animals, but their potential role in humans with alcohol dependence is poorly understood. We measured CB1 receptors in alcohol dependent patients in early and protracted abstinence, and in comparison with control subjects without alcohol use disorders, using positron emission tomography and [(18)F]FMPEP-d2, a radioligand for CB1 receptors. We scanned 18 male in-patients with alcohol dependence twice, within 3-7 days of admission from ongoing drinking, and after 2-4 weeks of supervised abstinence. Imaging data were compared with those from 19 age-matched healthy male control subjects. Data were also analyzed for potential influence of a common functional variation (rs2023239) in the CB1 receptor gene (CNR1) that may moderate CB1 receptor density. On the first scan, CB1 receptor binding was 20-30% lower in patients with alcohol dependence than in control subjects in all brain regions and was negatively correlated with years of alcohol abuse. After 2-4 weeks of abstinence, CB1 receptor binding remained similarly reduced in these patients. Irrespective of the diagnostic status, C allele carriers at rs2023239 had higher CB1 receptor binding compared with non-carriers. Alcohol dependence is associated with a widespread reduction of cannabinoid CB1 receptor binding in the human brain and this reduction persists at least 2-4 weeks into abstinence. The correlation of reduced binding with years of alcohol abuse suggests an involvement of CB1 receptors in alcohol dependence in humans.
Assuntos
Alcoolismo/metabolismo , Encéfalo/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Adulto , Alcoolismo/diagnóstico por imagem , Alelos , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Neuroimagem Funcional , Humanos , Masculino , CintilografiaRESUMO
Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB(1) (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB(1) receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After â¼4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB(1) receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB(1) receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Neuroimagem Funcional/psicologia , Fumar Maconha/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Adulto , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Radioisótopos de Flúor , Neuroimagem Funcional/métodos , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons/psicologia , Pirrolidinonas , Síndrome de Abstinência a Substâncias/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Short-term depletion of plasma tryptophan has been shown to result in depressive relapse in patients with remission of major depression. Positron emission tomography and single photon emission computed tomography studies implicated the dorsolateral prefrontal cortex, orbitofrontal cortex, thalamus, and caudate nucleus in the pathogenesis of depression. The purpose of this study was to measure cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. METHODS: Patients diagnosed as having major depression (N = 21) who clinically improved with serotonin reuptake inhibitors underwent 2 test days involving tryptophan depletion or placebo, followed 6 hours later by positron emission tomography scanning with fludeoxy-glucose F18. Brain metabolism was compared in patients with (n = 7) and without (n = 14) a tryptophan depletion-induced depressive relapse. RESULTS: Tryptophan depletion resulted in a decrease in brain metabolism in the middle frontal gyrus (dorsolateral prefrontal cortex), thalamus, and orbitofrontal cortex in patients with a depletion-induced depressive relapse (but not in patients without depletion-induced relapse). Decreased brain metabolism in these regions correlated with increased depressive symptoms. Baseline metabolism was increased in prefrontal and limbic regions in relapse-prone patients. CONCLUSION: Specific brain regions, including the middle frontal gyrus, thalamus, and orbitofrontal cortex, may mediate the symptoms of patients with major depression.
Assuntos
Encéfalo/diagnóstico por imagem , Transtorno Depressivo/diagnóstico por imagem , Transtorno Depressivo/fisiopatologia , Serotonina/fisiologia , Tomografia Computadorizada de Emissão , Triptofano/metabolismo , Antidepressivos/uso terapêutico , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Desoxiglucose/análogos & derivados , Transtorno Depressivo/tratamento farmacológico , Método Duplo-Cego , Fluordesoxiglucose F18 , Glucose/metabolismo , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/metabolismo , Sistema Límbico/fisiopatologia , Placebos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Escalas de Graduação Psiquiátrica , Recidiva , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Tálamo/fisiopatologia , Triptofano/administração & dosagem , Triptofano/sangueRESUMO
BACKGROUND: We have previously reported an increase in symptoms of anxiety in patients with posttraumatic stress disorder (PTSD) following administration of the beta 2-antagonist yohimbine, which stimulates brain norepinephrine release. Preclinical studies show decreased metabolism in the neocortex and the caudate nucleus with high-dose yohimbine-induced norepinephrine release, but low levels of norepinephrine release result in an increase in metabolism in these areas. METHODS: We used positron emission tomography and fludeoxyglucose F 18 to measure brain metabolism in Vietnam combat veterans with PTSD (n = 10) and healthy age-matched control subjects (n = 10), following administration of yohimbine (0.4 mg/kg) or placebo in a randomized, double-blind fashion. RESULTS: Yohimbine resulted in a significant increase in anxiety in the patients with PTSD, but not in healthy subjects. There was a significant difference in brain metabolic response to yohimbine in patients with PTSD compared with healthy subjects in prefrontal, temporal, parietal, and orbitofrontal cortexes. Metabolism tended to decrease in patients with PTSD and increase in healthy subjects following administration of yohimbine. CONCLUSION: These findings are consistent with our previous hypothesis of enhanced norepinephrine release in the brain with yohimbine in patients with PTSD.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Norepinefrina/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Tomografia Computadorizada de Emissão , Ioimbina/farmacologia , Transtornos de Ansiedade/induzido quimicamente , Transtornos de Ansiedade/metabolismo , Química Encefálica/efeitos dos fármacos , Desoxiglucose/análogos & derivados , Desoxiglucose/metabolismo , Fluordesoxiglucose F18 , Glucose/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Ioimbina/metabolismoRESUMO
Neurochemical brain imaging methods developed over the past 20 years offer significant promise for elucidating the biochemical underpinnings of schizophrenia. The two general methodologies used for these studies have been: 1) radiotracer imaging: PET (positron emission tomography) and SPECT (single photon emission computed tomography); and 2) NMR (nuclear magnetic resonance) imaging: fMRI (functional magnetic resonance imaging) and MRS (magnetic resonance spectroscopy). Despite conflicting findings, striatal D2 receptor density may be elevated in some, but not all patients. Elevated synthesis, and increased release of dopamine after amphetamine challenge have also been reported. Imaging of cortical 5-HT2A receptors suggests that this system is unaffected, in conflict with findings of postmortem studies. Although prior postmortem studies suggested an increase in cortical GABAA receptors, three SPECT studies have found no significant changes. MRS studies have shown decreased levels of NAA (N-acetyl-aspartate) moieties in hippocampus and frontal cortex of schizophrenic patients, which is consistent with the reported loss of neurons and neuropil in postmortem brains. In conclusion, developments in radiotracer and NMR imaging have provided promising leads to the biochemical abnormalities associated with schizophrenia. Future significant understanding is likely to occur with the development of new probes and enhanced instrument technology, when applied with an appreciation of the heterogeneity of the disorder and the need for careful clinical assessment of patients.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada de Emissão , Ácido Aspártico/metabolismo , Encéfalo/anatomia & histologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Ácido Homovanílico/metabolismo , Humanos , Imageamento por Ressonância Magnética , Receptores de Dopamina D2/metabolismo , Receptores de GABA/metabolismo , Serotonina/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
The recent development of [carbonyl-(11)C]WAY-100635 for serotonin (5-HT)(1A) and [(18)F]setoperone and [(18)F]altanserin for 5-HT(2A) positron emission tomography receptor imaging has allowed studies of 5-HT neurotransmission in depressive disorders. The hippocampus is likely to be an important brain structure in the pathophysiology of depression because it may mediate both cognitive deficits and hypercortisolemia found in this disorder. Decreased 5-HT(1A) binding was reported in the medial temporal cortex, which receives dense 5-HT innervation, and also throughout neocortical regions. Because the 5-HT(1A) antagonist pindolol may hasten antidepressant effects of selective serotonin reuptake inhibitor medications, its receptor occupancy has been measured in both presynaptic and postsynaptic sites. The results are controversial but suggest that pindolol has preferential occupancy of somatodendritic autoreceptors in the raphe. The results of 5-HT(2A) receptors are mixed, with one showing a significant decrease in the right orbitoinsular cortex and three not detecting a significant change. The disparate findings in patients with depression almost certainly reflect the heterogeneity of the disorder, and we highlight the utility of the hippocampus as a useful target region not only to compare depressed subjects with healthy subjects but also to correlate findings with cognitive function and activity of the limbic-hypothalamic-pituitary axis system.
Assuntos
Encéfalo/fisiopatologia , Transtorno Depressivo/complicações , Receptores de Serotonina/fisiologia , Transmissão Sináptica/fisiologia , Tomografia Computadorizada de Emissão , Atrofia/etiologia , Atrofia/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Transtorno Depressivo/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Receptores Pré-Sinápticos/metabolismoRESUMO
For nearly three decades, evidence supporting a role for aberrant serotonergic function in the pathogenesis of depression has accumulated; however, only recently have methodologies and radiotracers suitable for in vivo clinical assessment of depression become available. To date, only a few neurochemical imaging studies have been performed in actively depressed subjects. A preliminary study using single photon emission computed tomography (SPECT) has demonstrated decreased levels of serotonin (5-HT) transporters in the midbrain regions of subjects with major depression. Analysis of the 5-HT2 receptor using positron emission tomography (PET) has suggested that this receptor may not be altered significantly in the depressed brain but may increase in response to antidepressant treatment. These findings are supported by studies in secondary "poststroke" depression that have shown that elevations in 5-HT2 receptor density correlated with the alleviation of symptoms of depressed mood. With the rapid development of novel PET and SPECT radiotracers, future studies of the serotonergic system that evaluate presynaptic (5-HT transporter) and postsynaptic (5-HT1A and 5-HT2A receptors) markers and the interaction of synaptic levels of 5-HT with these sites will make profound contributions to the understanding of the role of the serotonergic synapse in the pathophysiology of depression.
Assuntos
Transtorno Depressivo/patologia , Sistema Nervoso/patologia , Serotonina/fisiologia , Animais , Transtorno Depressivo/metabolismo , Humanos , Sistema Nervoso/metabolismo , Receptores de Serotonina/metabolismoRESUMO
BACKGROUND: Abnormalities of dopamine function in schizophrenia are suggested by the common antidopaminergic properties of antipsychotic medications. However, direct evidence of a hyperdopaminergic state in schizophrenia has been difficult to demonstrate, given the difficulty to measure dopamine transmission in the living human brain. Such evidence has recently emerged. Three studies reported an increase in dopamine transmission following acute amphetamine challenge in patients with schizophrenia compared to matched healthy control subjects, thus demonstrating a dysregulation of dopamine in schizophrenia. In all studies, a large variance was observed within the schizophrenic group in the magnitude of this finding, and clinical predictors of this effect could not be identified. METHODS: In this paper, we combined previously published and newly acquired data to obtain sufficient power to address this question. RESULTS: The most important findings derived from this extended data set are: 1) dysregulation of dopamine function revealed by the amphetamine challenge is present at onset of illness and in patients never previously exposed to neuroleptic medications; 2) this dysregulation was observed in patients experiencing an episode of illness exacerbation, but not in patients studied during a remission phase. CONCLUSIONS: A hyperdopaminergic state is present in schizophrenia during the initial episode and subsequent relapses, but not in periods of remission. This finding has important consequences for the development of new treatment strategies for the remission phase.
Assuntos
Dopamina/metabolismo , Esquizofrenia/metabolismo , Transmissão Sináptica/fisiologia , Adulto , Anfetaminas/sangue , Anfetaminas/farmacocinética , Encéfalo/diagnóstico por imagem , Cromatografia Líquida de Alta Pressão/métodos , Estudos de Coortes , Corpo Estriado/metabolismo , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Esquizofrenia/diagnóstico por imagem , Psicologia do Esquizofrênico , Índice de Gravidade de Doença , Fatores Sexuais , Estresse Psicológico/psicologia , Tomografia Computadorizada de Emissão , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
We have previously reported smaller hippocampal volume and deficits in short-term memory in patients with combat-related posttraumatic stress disorder (PTSD) relative to comparison subjects. The purpose of this study was to compare hippocampal volume in adult survivors of childhood abuse to matched controls. Magnetic resonance imaging was used to measure volume of the hippocampus in adult survivors of childhood abuse (n = 17) and healthy subjects (n = 17) matched on a case-by-case basis for age, sex, race, handedness, years of education, body size, and years of alcohol abuse. All patients met criteria for PTSD secondary to childhood abuse. PTSD patients had a 12% smaller left hippocampal volume relative to the matched controls (p < .05), without smaller volumes of comparison regions (amygdala, caudate, and temporal lobe). The findings were significant after controlling for alcohol, age, and education, with multiple linear regression. These findings suggest that a decrease in left hippocampal volume is associated with abuse-related PTSD.
Assuntos
Abuso Sexual na Infância/diagnóstico , Maus-Tratos Infantis/diagnóstico , Hipocampo/patologia , Imageamento por Ressonância Magnética , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Adulto , Alcoolismo/diagnóstico , Alcoolismo/psicologia , Mapeamento Encefálico , Criança , Maus-Tratos Infantis/psicologia , Abuso Sexual na Infância/psicologia , Comorbidade , Dominância Cerebral/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/psicologiaRESUMO
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.
Assuntos
Tronco Encefálico/metabolismo , Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Radioisótopos do Iodo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Neostriado/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Fatores Etários , Tronco Encefálico/diagnóstico por imagem , Estudos de Casos e Controles , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
BACKGROUND: Alterations in benzodiazepine receptor function have long been hypothesized to play a role in anxiety. Animal models of anxiety involving exposure to chronic stress have shown a specific decrease in benzodiazepine receptor binding in frontal cortex and hippocampus. The purpose of this study was to examine benzodiazepine receptor binding patients with panic disorder and comparison subjects. METHODS: A quantitative measure related to benzodiazepine receptor binding (Distribution Volume (DV)) was obtained with single photon emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement of radioligand concentration in plasma in patients with panic disorder and healthy controls. DV image data were analyzed using statistical parametric mapping (spm96). RESULTS: A decrease in measures of benzodiazepine receptor binding (DV) was found in left hippocampus and precuneus in panic disorder patients relative to controls. Panic disorder patients who had a panic attack compared to patients who did not have a panic attack at the time of the scan had a decrease in benzodiazepine receptor binding in prefrontal cortex. CONCLUSIONS: Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor binding may be related to alterations in benzodiazepine receptor binding, or other factors including changes in GABAergic transmission or possible endogenous benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex appears to be involved in changes in state-related panic anxiety.
Assuntos
Flumazenil/análogos & derivados , Radioisótopos do Iodo , Transtorno de Pânico/diagnóstico por imagem , Transtorno de Pânico/metabolismo , Receptores de GABA-A/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Adolescente , Adulto , Idoso , Feminino , Moduladores GABAérgicos/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/patologiaRESUMO
BACKGROUND: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. METHODS: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. RESULTS: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). CONCLUSIONS: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.
Assuntos
Antidepressivos/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Proteínas de Transporte/fisiologia , Cocaína/análogos & derivados , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/fisiopatologia , Glicoproteínas de Membrana/fisiologia , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Serotonina/fisiologia , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Antidepressivos/uso terapêutico , Tronco Encefálico/fisiopatologia , Cocaína/farmacocinética , Cocaína/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paroxetina/sangue , Escalas de Graduação Psiquiátrica , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
The in vivo kinetics of the dopamine (DA) transporter probe 123I-labeled 2 beta-carboxymethoxy-3 beta-(4-iodophenyl) tropane ([123I] beta-CIT) in striatum was investigated with single-photon emission computerized tomography (SPECT) in five healthy human subjects. The aim of this study was to derive an adequate measure of the DA transporter density that would not be affected by regional cerebral blood flow or peripheral clearance of the tracer. SPECT data were acquired on the day of injection (day 1) from 0 to 7 h and on the following day (day 2) from 19 to 25 h. Arterial sampling on day 1 was used to measure the input function. Graphical, kinetic, and equilibrium analyses were evaluated. Graphical analysis of day 1 data, with the assumption of negligible dissociation of the tracer-receptor complex (k4 = 0), was found to be blood flow-dependent. A three-compartment kinetic analysis of day 1 data were performed using a three (k4 = 0)- and a four (k4 > 0)-parameter model. The three-parameter model estimated the konBmax product at 0.886 +/- 0.087 min-1. The four-parameter model gave a binding potential (BP) of 476 ml g-1, a value consistent with in vitro measurements. The stability of the regional uptake on day 2 allowed direct measurement of the specific to nonspecific equilibrium partition coefficient (V3" = k3/k4 = 6.66 +/- 1.54). Results of day 1 kinetic analysis and day 2 equilibrium analysis were well correlated among subjects. Simulations indicated that the error associated with the day 2 equilibrium analysis was acceptable for plasma tracer terminal half-lives > 10 h. We propose the equilibrium analysis on day 2 as the method of choice for clinical studies since it does not require multiple scans or the measurement of the arterial plasma tracer concentrations.
Assuntos
Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Adulto , Encéfalo/diagnóstico por imagem , Cocaína/sangue , Cocaína/metabolismo , Simulação por Computador , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Radioisótopos do Iodo , Cinética , Masculino , Modelos Biológicos , Proteínas do Tecido Nervoso/metabolismo , Valores de Referência , Fatores de Tempo , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
In vivo benzodiazepine receptor equilibrium dissociation constant, KD, and maximum number of binding sites, Bmax, were measured by single photon emission computerized tomography (SPECT) in three baboons. Animals were injected with a bolus followed by a constant i.v. infusion of the high affinity benzodiazepine ligand [123I]iomazenil. Plasma steady-state concentration and receptor-ligand equilibrium were reached within 2 and 3 h, respectively, and were sustained for the duration (4-9 h) of the experiments (n = 15). At the end of the experiments, a receptor saturating dose of flumazenil (0.2 mg/kg) was injected to measure nondisplaceable activity. Experiments were carried out at various levels of specific activity, and Scatchard analysis was performed for derivation of the KD (0.59 +/- 0.09 nM) and Bmax (from 126 nM in the occipital region to 68 nM in the striatum). Two animals were killed and [125I]iomazenil Bmax and KD were measured at 22 and 37 degrees C on occipital homogenate membranes. In vitro values of Bmax (114 +/- 33 nM) and 37 degrees C KD (0.66 +/- 0.16 nM) were in good agreement with in vivo values measured by SPECT. This study demonstrates that SPECT can be used to quantify central neuroreceptors density and affinity.
Assuntos
Flumazenil/análogos & derivados , Receptores de GABA-A/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Animais , Sangue/metabolismo , Feminino , Flumazenil/metabolismo , Homeostase , Técnicas In Vitro , Radioisótopos do Iodo , Cinética , PapioRESUMO
Postmortem studies have provided limited and conflicting data regarding aging effects on the central serotonin transporter (SERT). The present study investigated the effect of age on SERT availability in the human brainstem and diencephalon with single photon emission computed tomography (SPECT) using the ligand [(123)I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([(123)I]beta-CIT). Healthy control subjects (n = 126) who ranged in age from 18 to 88 were injected with 6.0 +/- 0.8 (mean +/- SD) mCi [(123)I]beta-CIT and imaged 23.1 +/- 1.9 h later under equilibrium conditions. A ratio of specific to nondisplaceable brain uptake (i.e. , V(3)" = [brainstem-diencephalon -occipital]/occipital), a measure proportional to the binding potential (B(max)/K(D)), was derived. SERT availability (V(3)") showed a significant inverse correlation with age (r = -0.40, P < 0.0001). Linear regression analysis revealed that V(3)" declined by 29.5% over the age range 18 to 88, or approximately 4.2% per decade. These results demonstrate reductions in the availability of central SERT binding sites with age in living human subjects.
Assuntos
Envelhecimento/metabolismo , Química Encefálica/fisiologia , Proteínas de Transporte/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Tomografia Computadorizada de Emissão de Fóton Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Tronco Encefálico/química , Tronco Encefálico/fisiologia , Cocaína/análogos & derivados , Diencéfalo/química , Diencéfalo/fisiologia , Feminino , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Valores de Referência , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
OBJECTIVE: Animals exposed to stress exhibit a decrease in benzodiazepine receptor binding in the frontal cortex. No studies have examined central benzodiazepine receptor binding in patients with posttraumatic stress disorder (PTSD). The purpose of this study was to examine measures of benzodiazepine receptor binding in PTSD. METHOD: From 13 patients with Vietnam combat-related PTSD and 13 case-matched healthy comparison subjects, a quantitative measure related to benzodiazepine receptor binding (distribution volume) was obtained with single photon emission computed tomography (SPECT) imaging of [(123)I]iomazenil binding and measurement of radioligand concentration in plasma. Distribution volume image data were analyzed by means of statistical parametric mapping. RESULTS: Lower distribution volumes were found in the prefrontal cortex (Brodmann's area 9) of PTSD patients than in comparison subjects. CONCLUSIONS: These findings of lower values for the benzodiazepine receptor binding measure of distribution volume are consistent with fewer benzodiazepine receptors and/or reduced affinity of receptor binding in the medial prefrontal cortex in patients with PTSD. Alterations in benzodiazepine receptor function in this area may underlie many of the symptoms of PTSD.
Assuntos
Distúrbios de Guerra/diagnóstico , Córtex Pré-Frontal/metabolismo , Receptores de GABA-A/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/estatística & dados numéricos , Adulto , Escalas de Graduação Psiquiátrica Breve/estatística & dados numéricos , Distúrbios de Guerra/metabolismo , Distúrbios de Guerra/fisiopatologia , Flumazenil/análogos & derivados , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Radioisótopos do Iodo , Masculino , Mesencéfalo/diagnóstico por imagem , Mesencéfalo/metabolismo , Pessoa de Meia-Idade , Ponte/diagnóstico por imagem , Ponte/metabolismo , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Receptores de GABA-A/fisiologia , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Veteranos/psicologia , VietnãRESUMO
OBJECTIVE: Evidence of a relationship between genotype and binding availability was assessed for the dopamine and serotonin transporter genes. METHOD: The authors assessed dopamine transporter genotype at the SLC6A3 3' variable number of tandem repeats (VNTR) polymorphism and serotonin transporter genotype at the SLC6A4 promotor VNTR polymorphism in 30 healthy subjects who also underwent single photon emission computed tomography with [(123)I]beta-CIT. RESULTS: Subjects homozygous for the 10-repeat allele at the SLC6A3 locus demonstrated significantly lower dopamine transporter binding than carriers of the nine-repeat allele. There was no effect of SLC6A4 genotype upon serotonin transporter binding. CONCLUSIONS: These findings suggest that genetic variation at the SLC6A3 3' VNTR polymorphism may modify dopamine transporter function.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Dopamina/genética , Dopamina/metabolismo , Genótipo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Adulto , Proteínas de Transporte/isolamento & purificação , DNA/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/isolamento & purificação , Repetições Minissatélites/genética , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
OBJECTIVE: Increased dopaminergic neurotransmission has been implicated in the pathophysiology of bipolar disorder. However, it remains unclear whether the abnormality is due to increased dopamine release or enhanced postsynaptic receptor sensitivity. In this study, dopamine receptor imaging combined with a pharmacological challenge of amphetamine was used to assess both pre- and postsynaptic aspects of dopamine neurotransmission in euthymic bipolar disorder patients. METHOD: Thirteen patients with bipolar disorder (seven medication free and six receiving mood stabilizer therapy) who had been euthymic for more than 4 weeks and 13 age- and gender-matched healthy comparison subjects were included in the study. Single photon emission computed tomography scans were obtained with the striatal dopamine (D(2)/D(3)) receptor radiotracer iodobenzamide ([(123)I]IBZM) before and after an intravenous amphetamine challenge (0.3 mg/kg). Reduction in striatal [(123)I]IBZM binding potential from the first scan to the second scan was used as an indirect measure of the amount of dopamine released. Behavioral response to amphetamine was measured with the Brief Psychiatric Rating Scale, Young Mania Rating Scale, and visual analogue scales. RESULTS: Bipolar patients and healthy subjects did not differ in terms of mood state or striatal D(2) receptor binding at baseline. Amphetamine challenge led to a significantly greater behavioral response in bipolar patients than in healthy subjects. However, there was no significant difference between the two groups in the amphetamine-induced decrease in striatal [(123)I]IBZM binding. CONCLUSIONS: In a group of euthymic patients with bipolar disorder, this study did not find evidence for increased striatal dopamine release. Instead, these data are consistent with enhanced postsynaptic dopamine responsivity in patients with bipolar disorder.
Assuntos
Anfetamina/farmacologia , Transtorno Bipolar/fisiopatologia , Encéfalo/diagnóstico por imagem , Dopamina/metabolismo , Receptores Dopaminérgicos/efeitos dos fármacos , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Benzamidas/metabolismo , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Antagonistas de Dopamina/metabolismo , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Radioisótopos do Iodo/metabolismo , Masculino , Pulso Arterial , Pirrolidinas/metabolismo , Receptores Dopaminérgicos/metabolismoRESUMO
OBJECTIVE: Recent work has underscored the role of serotonergic neurotransmission in chronic neural adaptations to cocaine dependence. The authors tested for evidence of serotonergic dysfunction during acute abstinence from cocaine, a period of high risk for relapse in cocaine dependence. METHOD: Binding availability of dopamine transporters and serotonin transporters was measured in 15 cocaine-dependent subjects during acute abstinence and in 37 healthy comparison subjects by using [(123)I]beta-CIT and single photon emission computed tomography. RESULTS: Significant increases in diencephalic and brainstem serotonin transporter binding (16.7% and 31.6%, respectively) were observed in cocaine-dependent subjects. Brainstem serotonin transporter binding was significantly inversely correlated with age across diagnostic groups. CONCLUSIONS: These findings provide further evidence of serotonergic dysfunction during acute abstinence from chronic cocaine use. Age-related decline in brainstem serotonin transporter binding may underlie the poor response to selective serotonin reuptake inhibitor antidepressants seen in some elderly depressed patients.