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Objective: The COVID-19 pandemic served as an impetus for the rapid expansion of telehealth. In this study, we examined the experience of rapid transition to telemental health (TMH) within The Family Health Centers at NYU Langone, a large, urban, Federally Qualified Health Center, in the 3 months after the onset of the COVID-19 pandemic. Methods: We administered surveys to clinicians and patients who utilized TMH between March 16, 2020 and July 16, 2020. Patients were sent a web-based survey via email or received a phone survey (for those without email) with four languages choices: English, Spanish, Traditional Chinese, or Simplified Chinese. Results: The majority (79%) of clinicians (n = 83) rated the experience of TMH as "excellent" or "good," and felt that they could establish and maintain the patient relationship through TMH. Four thousand seven hundred seventy-two survey invitations were sent out to patients, and 654 (13.7%) responded. Ninety percent reported that they were satisfied with the service they received and rated TMH as better or the same as in-person care (81.6%) with a high mean satisfaction score (4.5 out of 5). Patients were more likely to rate TMH as better or the same as in-person care relative to the clinicians. Conclusions: These results are consistent with several recent studies that have explored patient satisfaction with TMH during the COVID-19 pandemic and demonstrate that both clinicians and patients experienced a high degree of satisfaction with mental health care delivered virtually compared with face-to-face encounters.
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COVID-19 , Serviços de Saúde Mental , Telemedicina , Humanos , COVID-19/epidemiologia , Pandemias , Satisfação do Paciente , Telemedicina/métodos , Instituições de Assistência Ambulatorial , Satisfação PessoalRESUMO
A large number of individuals in the US have experienced childhood trauma. However, little is known about the prevalence of trauma in a diverse patient population entering treatment in a community mental health center. To assess early trauma in this population, the Adverse Childhood Experience (ACEs) questionnaire was administered to 856 participants over a nine-month period. 40% reported four or more ACEs. Among high scorers, emotional abuse, physical abuse and emotional neglect were the most prevalent ACE experiences. High mean ACE sum scores were observed among patients with PTSD, depression, impulse disorder and substance use disorder. Having a higher ACE sum score was associated with a greater number of co-occurring psychiatric disorders. Characterizing ACEs by patient sociodemographic attributes and psychiatric diagnoses extracted from the electronic medical records (EMR) can benefit therapeutic interventions. These findings indicate a need for creating more trauma-informed settings with knowledgeable, trained staff.
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Experiências Adversas da Infância , Transtornos Relacionados ao Uso de Substâncias , Humanos , Saúde Mental , Prevalência , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
BACKGROUND: The dopamine (DA) hypothesis postulates hyperactivity of subcortical DA transmission and hypoactivity of cortical DA in schizophrenia (SCH). Positron emission tomography provides the ability to assess this hypothesis in humans. However, no studies have examined the relationship between cortical DA and striatal DA in this illness. METHODS: D2/3 receptor radiotracer [11C]FLB457 BPND (binding potential relative to nondisplaceable uptake) was measured in 14 off-medication subjects with SCH and 14 healthy control (HC) subjects at baseline and after the administration of 0.5 mg/kg oral d-amphetamine. The amphetamine-induced change in BPND (ΔBPND) was calculated as the difference between BPND in the postamphetamine condition and BPND in the baseline condition and expressed as a percentage of BPND at baseline. DA release in the striatum using the radiotracer [11C]NPA was also measured in these subjects. RESULTS: [11C]FLB457 ΔBPND was greater in the HC group compared with the SCH group (F1,26 = 5.7; p = .02) with significant differences in [11C]FLB457 ΔBPND seen across cortical brain regions. Only in the SCH group was a significant negative correlation observed between [11C]FLB457 ΔBPND in the dorsolateral prefrontal cortex and [11C]NPA ΔBPND in the dorsal caudate (r = -0.71, p = .005). CONCLUSIONS: Subjects with SCH demonstrated deficits of DA release in cortical brain regions relative to HC subjects. Examining both cortical and striatal DA release in the same subjects demonstrated an inverse relationship between cortical DA release and striatal DA release in SCH not present in HC subjects, providing support for the current DA hypothesis of SCH.
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Dopamina , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Anfetamina/farmacologia , Tomografia por Emissão de Pósitrons/métodos , DextroanfetaminaRESUMO
The widespread prevalence of coronavirus disease 2019 (COVID-19) means that inpatient psychiatric units will necessarily manage patients who have COVID-19 that is comorbid with acute psychiatric symptoms. We report a case of recurrence of respiratory symptoms and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription-polymerase chain reaction (RT-PCR) testing in a patient on an inpatient psychiatric unit occurring 42 days after the initial positive SARS-CoV-2 RT-PCR test, 38 days after initial symptom resolution, and 30 days after the first of 3 negative SARS-CoV-2 RT-PCR tests. Over the course of the admission, the patient was safely initiated on clozapine. Recent literature on COVID-19's potential recurrence and neuropsychiatric effects is reviewed and implications for the management of COVID-19 on inpatient psychiatric units are discussed. In the era of COVID-19 and our still-developing understanding of this illness, psychiatrists' role as advocates and collaborators in our patients' physical health care has become even more critical.
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Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , COVID-19/complicações , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/tratamento farmacológico , Transtornos Psicóticos/complicações , Transtornos Psicóticos/tratamento farmacológico , Adulto , Alcoolismo/complicações , Alcoolismo/diagnóstico , COVID-19/diagnóstico , COVID-19/psicologia , Teste de Ácido Nucleico para COVID-19 , Clozapina , Transtorno Depressivo Maior/diagnóstico , Hospitais Psiquiátricos , Humanos , Pacientes Internados/psicologia , Masculino , Mirtazapina/uso terapêutico , Transtornos Psicóticos/diagnóstico , Recidiva , SARS-CoV-2 , Sertralina/uso terapêutico , Tentativa de SuicídioRESUMO
BACKGROUND: New York City's first case of SARS-associated coronavirus (SARS-CoV-2) disease 2019 (COVID-19) was identified on 1 March 2020, prompting rapid restructuring of hospital-based services to accommodate the increasing numbers of medical admissions. Non-essential services were eliminated but in-patient treatment of psychiatric illnesses was necessarily maintained. AIMS: To detail the response of the NYU Langone Health in-patient psychiatric services to the COVID-19 outbreak from 1 March to 1 May 2020. METHOD: Process improvement/quality improvement study. RESULTS: Over this time period, our two in-patient psychiatric units (57 total beds) treated 238 patients, including COVID-19-positive and -negative individuals. Testing for COVID-19 was initially limited to symptomatic patients but expanded over the 62-day time frame. In total, 122 SARS-CoV-2 polymerase chain reaction (PCR) tests were performed in 98 patients. We observed an overall rate of COVID-19 infection of 15.6% in the patients who were tested, with an asymptomatic positive rate of 13.7%. Although phased roll-out of testing impaired the ability to fully track on-unit transmission of COVID-19, 3% of cases were clearly identified as results of on-unit transmission. CONCLUSIONS: Our experience indicates that, with appropriate precautions, patients in need of in-patient psychiatric admission who have COVID-19 can be safely managed. We provide suggested guidelines for COVID-19 management on in-patient psychiatric units which incorporate our own experiences as well as published recommendations.
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BACKGROUND: Positron emission tomography studies have demonstrated less dopamine D2/3 receptor availability and blunted psychostimulant-induced dopamine release in cocaine-dependent subjects (CDSs). No studies in CDSs have reported the in vivo status of D2/3 and dopamine release in the cortex. Basic and functional imaging studies suggest a role for prefrontal cortical dopaminergic abnormalities in impaired executive function and relapse in cocaine dependence. We used [11C]FLB 457 positron emission tomography and amphetamine to measure cortical D2/3 receptors and dopamine release in CDSs. METHODS: [11C]FLB 457 and positron emission tomography were used to measure D2/3 receptor binding potential in cortical regions of interest in recently abstinent CDSs (n = 24) and healthy control subjects (n = 36) both before and after 0.5 mg kg-1 of oral d-amphetamine. Binding potential relative to nondisplaceable uptake (BPND) and binding potential relative to total plasma concentration (BPP) were derived using an arterial input function-based kinetic analysis. Cortical dopamine release in regions of interest was measured as the change in BPND and BPP after amphetamine. RESULTS: Baseline D2/3 receptor availability (BPP and BPND) and amphetamine-induced dopamine release (ΔBPND and ΔBPP) were significantly lower in the cortical regions in CDSs compared with healthy control subjects. Fewer D2/3 receptors and less dopamine release in CDSs were not associated with performance on working memory and attention tasks. CONCLUSIONS: The results of this study suggest that deficits in dopamine D2/3 transmission involve the cortex in cocaine dependence. Further studies to understand the clinical relevance of these findings are warranted.
Assuntos
Transtornos Relacionados ao Uso de Cocaína , Dopamina , Anfetamina/farmacologia , Transtornos Relacionados ao Uso de Cocaína/diagnóstico por imagem , Humanos , Cinética , Tomografia por Emissão de Pósitrons , Pirrolidinas , SalicilamidasAssuntos
Dopamina , Esquizofrenia , Análise de Variância , Corpo Estriado , Humanos , Razão Sinal-RuídoRESUMO
Studies in nonhuman primates and humans have demonstrated that amphetamine-induced dopamine release in the cortex can be measured with [11 C]FLB 457 and PET imaging. This technique has been successfully used in recent clinical studies to show decreased dopamine transmission in the prefrontal cortex in schizophrenia and alcohol dependence. Here, we present data from a cohort of twelve healthy controls in whom an oral amphetamine challenge (0.5 mg kg-1 ) did not lead to a significant reduction in [11 C]FLB 457 BPND (i.e., binding potential relative to non-displaceable uptake). Two factors that likely contributed to the inability to displace [11 C]FLB 457 BPND in this cohort relative to successful cohorts are: (a) the acquisition of the baseline and post-amphetamine scans on different days as opposed to the same day and (b) the initiation of the post-amphetamine [11 C]FLB 457 scan at â¼5 hours as opposed to â¼3 hours following oral amphetamine. Furthermore, we show [11 C]FLB 457 reproducibility data from a legacy dataset to support greater variability in cortical BPND when the test and retest scans are acquired on different days as compared to the same day. These results highlight the methodological challenges that continue to plague the field with respect to imaging dopamine release in the cortex.
Assuntos
Anfetamina/farmacologia , Encéfalo , Antagonistas de Dopamina/farmacocinética , Inibidores da Captação de Dopamina/farmacologia , Tomografia por Emissão de Pósitrons , Pirrolidinas/farmacocinética , Salicilamidas/farmacocinética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Mapeamento Encefálico , Radioisótopos de Carbono/sangue , Radioisótopos de Carbono/farmacocinética , Antagonistas de Dopamina/sangue , Feminino , Humanos , Masculino , Pirrolidinas/sangue , Salicilamidas/sangue , Adulto JovemRESUMO
BACKGROUND: Receptor imaging studies have reported increased amphetamine-induced dopamine release in subjects with schizophrenia (SCH) relative to healthy control subjects (HCs). A limitation of these studies, performed with D2/3 antagonist radiotracers, is the failure to provide information about D2/3 receptors configured in a state of high affinity for the agonists (i.e., D2/3 receptors coupled to G proteins [D2/3 HIGH]). The endogenous agonist dopamine binds with preference to D2/3 HIGH receptors relative to D2/3 LOW receptors, making it critical to understand the status of D2/3 HIGH receptors in SCH. METHODS: D2/3 agonist positron emission tomography radiotracer [11C]N-propyl-norapomorphine ([11C]NPA) binding potential (BPND) was measured in 14 off-medication subjects with SCH and 14 matched HCs at baseline and after the administration of 0.5 mg kg-1 oral D-amphetamine. The amphetamine-induced change in BPND (ΔBPND) was calculated as the difference between BPND in the postamphetamine condition and BPND in the baseline condition and was expressed as a percentage of BPND at baseline. RESULTS: A trend-level increase was observed in comparing baseline [11C]NPA BPND (repeated-measures analysis of variance, F1,26 = 3.34, p = .08) between the SCH and HC groups. Amphetamine administration significantly decreased BPND in all striatal regions across all subjects in both groups. No differences were observed in [11C]NPA ΔBPND (repeated-measures analysis of variance, F1,26 = 1.9, p = .18) between HCs and subjects with SCH. Amphetamine significantly increased positive symptoms in subjects with SCH (19.5 ± 5.3 vs. 23.7 ± 4.1, paired t test, p < .0001); however, no correlations were noted with [11C]NPA BPND or ΔBPND. CONCLUSIONS: This study provides in vivo indication of a role for postsynaptic factors in amphetamine-induced psychosis in SCH.
Assuntos
Anfetamina/farmacologia , Apomorfina/análogos & derivados , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/farmacocinética , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Esquizofrenia/metabolismo , Adolescente , Adulto , Apomorfina/farmacocinética , Corpo Estriado/diagnóstico por imagem , Feminino , Humanos , Masculino , Traçadores Radioativos , Esquizofrenia/diagnóstico por imagem , Adulto JovemRESUMO
SEP-227162 [R(-)-O-desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O-desmethylvenlafaxine (ODV, Pristiq™, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP-227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [11 C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP-227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [11 C]DASB. A baseline, off-medication, scan was performed prior to dosing and a [11 C]DASB PET scan was performed after 72 hr at each dose level. [11 C]DASB binding potential (BPND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BPND (ΔBPND ) from baseline scan to the on-medication scan relative to the baseline BPND value. SEP-227162 and ODV significantly reduced regional distribution volumes and region BPND values in a dose-dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP-227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.
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Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Succinato de Desvenlafaxina/análogos & derivados , Succinato de Desvenlafaxina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Adulto , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Succinato de Desvenlafaxina/sangue , Relação Dose-Resposta a Droga , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Inibidores da Recaptação de Serotonina e Norepinefrina/sangue , Sulfetos , Adulto JovemRESUMO
ONO-2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO-specific PET radioligand [11 C]PBR28 to confirm binding of ONO-2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO-2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO-2952 (n = 4 per dose). Two PET scans with [11 C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO-2952 administration. [11 C]PBR28 regional distribution volume (VT ) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (VND ) was obtained on an individual basis for each subject using linear regression as the x-intercept of the Lassen plot. The binding potential relative to VND (BPND ) was derived as the difference between VT in the ROI (VT ROI) and VND , normalized to VND ; BPND = (VT ROI - VND )/VND . TSPO occupancy was calculated as the change in BPND (ΔBPND ) from individual's baseline scan to the on-medication scan to the baseline BPND value. TSPO occupancy by ONO-2952 was dose dependent between 20-200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated Ki values ranged from 24.1 to 72.2 nM. This open-label, single-center, single-dose study demonstrated engagement of ONO-2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO-2952 could potentially modulate neurosteroid production by binding to brain TSPO.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ciclopropanos/farmacologia , Antagonistas GABAérgicos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Receptores de GABA/metabolismo , Acetamidas , Adulto , Radioisótopos de Carbono , Ciclopropanos/efeitos adversos , Ciclopropanos/sangue , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Antagonistas GABAérgicos/efeitos adversos , Antagonistas GABAérgicos/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/sangue , Humanos , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Piridinas , Compostos Radiofarmacêuticos , Adulto JovemRESUMO
Basic investigations link a Val158Met polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene to not only its enzymatic activity, but also to its dopaminergic tone in the prefrontal cortex. Previous PET studies have documented the relationship between COMT Val158Met polymorphism and D1 and D2/3 receptor binding potential (BP), and interpreted them in terms of dopaminergic tone. The use of baseline dopamine D1 and D2/3 receptor binding potential (BPND) as a proxy for dopaminergic tone is problematic because they reflect both endogenous dopamine levels (a change in radiotracer's apparent affinity) and receptor density. In this analysis of 31 healthy controls genotyped for the Val158Met polymorphism (Val/Val, Val/Met, and Met/Met), we used amphetamine-induced displacement of [11C]FLB 457 as a direct measure of dopamine release. Our analysis failed to show a relationship between COMT genotype status and prefrontal cortical dopamine release. COMT genotype was also not predictive of baseline dopamine D2/3 receptor BPND.
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Anfetamina/farmacologia , Catecol O-Metiltransferase/genética , Córtex Cerebral/metabolismo , Dopamina/metabolismo , Tomografia por Emissão de Pósitrons , Pirrolidinas/farmacologia , Salicilamidas/farmacologia , Adulto , Córtex Cerebral/diagnóstico por imagem , Demografia , Feminino , Genótipo , Humanos , Masculino , Receptores Dopaminérgicos/metabolismoRESUMO
Changes in endogenous dopamine levels can be detected in humans using positron emission tomography scans by measuring the amount by which a specific D2/3 radioligand is displaced. In some cases, a challenge drug such as amphetamine is introduced to increase the amount of dopamine released into the synaptic cleft. Although intravenous amphetamine is often utilized, oral amphetamine has been shown to be just as effective in increasing endogenous dopamine levels. Based on our own use of oral amphetamine as a challenge drug, we have retroactively reviewed our study charts to determine the cardiovascular safety of 0.5 mg kg(-1) oral d-amphetamine. Of 172 amphetamine administrations in 144 individuals, only 2.8% of subjects experienced any transient adverse effects. In addition, we found no clinically relevant differences in increases of vital signs between healthy controls and patients. We therefore reaffirm the safety of 0.5 mg kg(-1) oral amphetamine in subjects previously screened for cardiovascular risk factors.
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Anfetamina/efeitos adversos , Tomografia por Emissão de Pósitrons , Administração Oral , Adolescente , Adulto , Anfetamina/administração & dosagem , Anfetamina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. METHOD: The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT). RESULTS: [(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power. CONCLUSIONS: This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.
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Esquizofrenia/diagnóstico por imagem , Psicologia do Esquizofrênico , Transmissão Sináptica , Lobo Temporal/diagnóstico por imagem , Ácido gama-Aminobutírico/metabolismo , Adulto , Radioisótopos de Carbono , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Feminino , Flumazenil , Moduladores GABAérgicos , Proteínas da Membrana Plasmática de Transporte de GABA , Ritmo Gama , Humanos , Masculino , Testes Neuropsicológicos , Inibidores da Captação de Neurotransmissores , Ácidos Nipecóticos , Tomografia por Emissão de Pósitrons , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Lobo Temporal/metabolismo , Lobo Temporal/fisiopatologia , Tiagabina , Adulto JovemRESUMO
OBJECTIVE: Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such as working memory, attention, inhibitory control, and risk/reward decisions, all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies of alcoholism that have demonstrated less dopamine in the striatum, the authors hypothesized decreased dopamine transmission in the prefrontal cortex in persons with alcohol dependence. METHOD: To test this hypothesis, amphetamine and [11C]FLB 457 positron emission tomography were used to measure cortical dopamine transmission in 21 recently abstinent persons with alcohol dependence and 21 matched healthy comparison subjects. [11C]FLB 457 binding potential, specific compared to nondisplaceable uptake (BPND), was measured in subjects with kinetic analysis using the arterial input function both before and after 0.5 mg kg-1 of d-amphetamine. RESULTS: Amphetamine-induced displacement of [11C]FLB 457 binding potential (ΔBPND) was significantly smaller in the cortical regions in the alcohol-dependent group compared with the healthy comparison group. Cortical regions that demonstrated lower dopamine transmission in the alcohol-dependent group included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex, and medial temporal lobe. CONCLUSIONS: The results of this study, for the first time, unambiguously demonstrate decreased dopamine transmission in the cortex in alcoholism. Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism.
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Alcoolismo/metabolismo , Dopamina/metabolismo , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica/fisiologia , Adolescente , Adulto , Alcoolismo/fisiopatologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiologia , Radioisótopos de Carbono , Estudos de Casos e Controles , Dextroanfetamina/farmacologia , Antagonistas de Dopamina , Inibidores da Captação de Dopamina/farmacologia , Feminino , Neuroimagem Funcional , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Pirrolidinas , Salicilamidas , Transmissão Sináptica/efeitos dos fármacos , Adulto JovemRESUMO
Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [(11)C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [(11)C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [(11)C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [(11)C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [(11)C]flumazenil VT in Group II in association cortices (6.8 ± 0.8 mL g-1 vs. 7.3 ± 0.4 mL g-1;p = 0.03), sensory cortices (6.7 ± 0.8 mL g-1 vs. 7.3 ± 0.5 mL g-1;p = 0.02) and limbic regions (5.2 ± 0.6 mL g-1 vs. 5.7 ± 0.3 mL g-1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [(11)C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA.
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Isótopos de Carbono/farmacologia , Flumazenil/farmacologia , Moduladores GABAérgicos/farmacologia , Ácidos Nipecóticos/farmacologia , Ácido gama-Aminobutírico/metabolismo , Adulto , Cognição , Relação Dose-Resposta a Droga , Eletroencefalografia/métodos , Eletrofisiologia , Feminino , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Humanos , Ligantes , Masculino , Modelos Estatísticos , Tomografia por Emissão de Pósitrons/métodos , Análise de Regressão , TiagabinaRESUMO
3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.
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Transtornos Relacionados ao Uso de Anfetaminas/patologia , Benzilaminas/farmacocinética , Fluorbenzenos/farmacocinética , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Neocórtex/diagnóstico por imagem , Piperidinas/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Mapeamento Encefálico , Radioisótopos de Carbono/farmacocinética , Feminino , Humanos , Masculino , Neocórtex/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Ligação Proteica/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adulto JovemRESUMO
OBJECTIVE: Genetic, pharmacologic, and physiological data suggest that individuals with anorexia nervosa (AN) have altered striatal dopamine (DA) function. METHOD: We used an amphetamine challenge and positron emission tomography [(11) C]raclopride paradigm to explore DA striatal transmission in 10 recovered (REC) AN compared with 9 control women (CW). RESULTS: REC AN and CW were similar for baseline, postamphetamine [(11) C]raclopride binding potential (BP(ND) ) and change (Δ) in BP(ND) for all regions. In CW, ventral striatum Δ BP(ND) was associated with euphoria (r = -0.76; p = 0.03), which was not found for REC AN. Instead, REC AN showed a significant relationship between anxiety and Δ BP(ND) in the precommissural dorsal caudate (r = -0.62, p = 0.05). DISCUSSION: REC AN have a positive association between endogenous DA release and anxiety in the dorsal caudate. This finding could explain why food-related DA release produces anxiety in AN, whereas feeding is pleasurable in healthy participants.
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Anfetamina/farmacologia , Anorexia Nervosa/psicologia , Ansiedade/metabolismo , Corpo Estriado/metabolismo , Dopaminérgicos/farmacologia , Dopamina/metabolismo , Adulto , Anorexia Nervosa/diagnóstico por imagem , Anorexia Nervosa/metabolismo , Ansiedade/diagnóstico por imagem , Ansiedade/psicologia , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Euforia/efeitos dos fármacos , Euforia/fisiologia , Feminino , Humanos , CintilografiaRESUMO
OBJECTIVE: Positron emission tomography (PET) imaging studies in cocaine abusers have shown that low dopamine release in the striatum following an amphetamine challenge is associated with higher relapse rates. One possible mechanism that might lead to lower amphetamine-induced dopamine release is low availability of dopamine storage vesicles in the presynaptic terminals for release. Consistent with this hypothesis, postmortem studies have shown low levels of vesicular monoamine transporter, type 2 (VMAT2), the membrane protein that regulates the size of the vesicular dopamine pool, in cocaine abusers relative to healthy subjects. To confirm the postmortem findings, the authors used PET and the VMAT2 radioligand [¹¹C]-(+)-dihydrotetrabenazine (DTBZ) to assess the in vivo VMAT2 availability in a group of 12 recently abstinent cocaine-dependent subjects and matched healthy comparison subjects. METHOD: [¹¹C]DTBZ nondisplaceable binding potential (BP(ND)) was measured by kinetic analysis using the arterial input function or, if arterial input was unavailable, by the simplified reference tissue method. RESULTS: [¹¹C]DTBZ BP(ND) was significantly lower in the cocaine abusers than in the comparison subjects in the limbic striatum (10.0% lower), associative striatum (-13.4%), and sensorimotor striatum (-11.5%). CONCLUSIONS: The results of this in vivo PET study confirm previous in vitro reports of low VMAT2 availability in the striatum of cocaine abusers. It also suggests a compensatory down-regulation of the dopamine storage vesicles in response to chronic cocaine abuse and/or a loss of dopaminergic terminals. Further research is necessary to understand the clinical relevance of this observation to relapse and outcome in abstinent cocaine abusers.