RESUMO
Risky decision-making is a common, heritable endophenotype seen across many psychiatric disorders. Its underlying genetic architecture is incompletely explored. We examined behavior in the Balloon Analogue Risk Task (BART), which tests risky decision-making, in two independent samples of European ancestry. One sample (n = 1138) comprised healthy participants and some psychiatric patients (53 schizophrenia, 42 bipolar disorder, 47 ADHD); the other (n = 911) excluded for recent treatment of various psychiatric disorders but not ADHD. Participants provided DNA and performed the BART, indexed by mean adjusted pumps. We constructed a polygenic risk score (PRS) for discovery in each dataset and tested it in the other as replication. Subsequently, a genome-wide MEGA-analysis, combining both samples, tested genetic correlation with risk-taking self-report in the UK Biobank sample and psychiatric phenotypes characterized by risk-taking (ADHD, Bipolar Disorder, Alcohol Use Disorder, prior cannabis use) in the Psychiatric Genomics Consortium. The PRS for BART performance in one dataset predicted task performance in the replication sample (r = 0.13, p = 0.000012, pFDR = 0.000052), as did the reciprocal analysis (r = 0.09, p = 0.0083, pFDR=0.04). Excluding participants with psychiatric diagnoses produced similar results. The MEGA-GWAS identified a single SNP (rs12023073; p = 3.24 × 10-8) near IGSF21, a protein involved in inhibitory brain synapses; replication samples are needed to validate this result. A PRS for self-reported cannabis use (p = 0.00047, pFDR = 0.0053), but not self-reported risk-taking or psychiatric disorder status, predicted behavior on the BART in our MEGA-GWAS sample. The findings reveal polygenic architecture of risky decision-making as measured by the BART and highlight its overlap with cannabis use.
Assuntos
Transtorno Bipolar , Esquizofrenia , Humanos , Transtorno Bipolar/genética , Esquizofrenia/genética , Fatores de Risco , Encéfalo , Consumo de Bebidas Alcoólicas , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Predisposição Genética para Doença/genéticaRESUMO
Chronic methamphetamine use poses potentially devastating consequences for directly affected individuals and for society. Lower dopamine D2-type receptor availability has been observed in striata of methamphetamine users as compared with controls, but an analogous comparison of D1-type receptors has been conducted only on post-mortem material, with no differences in methamphetamine users from controls in the caudate nucleus and putamen and higher D1-receptor density in the nucleus accumbens. Released from neurons when methamphetamine is self-administered, dopamine binds to both D1- and D2-type receptors in the striatum, with downstream effects on cortical activity. Thus, both receptor subtypes may contribute to methamphetamine-induced alterations in cortical morphology and behavior. In this study, 21 methamphetamine-dependent subjects and 23 healthy controls participated in positron emission tomography and structural magnetic resonance imaging for assessment of striatal D1- and D2-type receptor availability and cortical gray-matter thickness, respectively. Although D2-type receptor availability (BPnd) was lower in the methamphetamine group, as shown previously, the groups did not differ in D1-type BPnd. In the methamphetamine group, mean cortical gray-matter thickness was negatively associated with cumulative methamphetamine use and craving for the drug. Striatal D1-type but not D2-type BPnd was negatively associated with global mean cortical gray-matter thickness in the methamphetamine group, but no association was found between gray-matter thickness and BPnd for either dopamine receptor subtype in the control group. These results suggest a role of striatal D1-type receptors in cortical adaptation to chronic methamphetamine use.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Corpo Estriado/metabolismo , Receptores de Dopamina D1/metabolismo , Adulto , Estudos de Casos e Controles , Núcleo Caudado/metabolismo , Dopamina/farmacologia , Feminino , Substância Cinzenta/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Metanfetamina/farmacologia , Núcleo Accumbens/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D2/metabolismo , Adulto JovemRESUMO
Adding supraphysiologic doses of levothyroxine (L-T4) to standard treatment for bipolar depression shows promise, but the mechanisms underlying clinical improvement are unknown. In a previous pilot study, L-T4 treatment reduced depression scores and activity within the anterior limbic network. Here we extended this work in a randomized, double-blind, placebo-controlled study of patients with bipolar depression. Cerebral glucose metabolism was assessed with positron emission tomography and [F-18]fluorodeoxyglucose before and after 6 weeks of treatment with L-T4 (n=15) or placebo (n=10) in 12 volumes of interest (VOIs): the bilateral thalamus, amygdala, hippocampus, dorsal striatum and ventral striatum, and midline cerebellar vermis and subgenual cingulate cortex. Radioactivity in the VOIs, normalized to whole-brain radioactivity was taken as a surrogate index of glucose metabolism, and markers of thyroid function were assayed. Changes in brain activity and their association with clinical response were assessed using statistical parametric mapping. Adjunctive L-T4 treatment produced a significant decline in depression scores during the 6-week treatment. In patients treated with L-T4, we found a significant decrease in regional activity at P<0.05 after Bonferroni correction in the left thalamus, right amygdala, right hippocampus, left ventral striatum and the right dorsal striatum. Decreases in the left thalamus, left dorsal striatum and the subgenual cingulate were correlated with a reduction in depression scores (P<0.05 after Bonferroni correction). Placebo treatment was associated with a significant decrease in activity only in the right amygdala, and no region had a change in activity that was correlated with change in depression scores. The groups differed significantly in the relationship between the changes in depression scores and in activity in the thalamus bilaterally and the left ventral striatum. The findings provide evidence that administration of supraphysiologic thyroid hormone improves depressive symptoms in patients with bipolar disorder by modulating function in components of the anterior limbic network.
Assuntos
Transtorno Bipolar/metabolismo , Tiroxina/efeitos dos fármacos , Tiroxina/metabolismo , Adulto , Tonsila do Cerebelo/metabolismo , Transtorno Bipolar/tratamento farmacológico , Encéfalo/metabolismo , Mapeamento Encefálico , Depressão/complicações , Método Duplo-Cego , Feminino , Glucose/metabolismo , Giro do Cíngulo/metabolismo , Humanos , Sistema Límbico/metabolismo , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Placebos , Tomografia por Emissão de Pósitrons/métodos , Córtex Pré-Frontal/metabolismo , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
Stimulant use disorders are associated with deficits in striatal dopamine receptor availability, abnormalities in mesocorticolimbic resting-state functional connectivity (RSFC) and impulsivity. In methamphetamine-dependent research participants, impulsivity is correlated negatively with striatal D2-type receptor availability, and mesocorticolimbic RSFC is stronger than that in controls. The extent to which these features of methamphetamine dependence are interrelated, however, is unknown. This question was addressed in two studies. In Study 1, 19 methamphetamine-dependent and 26 healthy control subjects underwent [18F]fallypride positron emission tomography to measure ventral striatal dopamine D2-type receptor availability, indexed by binding potential (BPND), and functional magnetic resonance imaging (fMRI) to assess mesocorticolimbic RSFC, using a midbrain seed. In Study 2, an independent sample of 20 methamphetamine-dependent and 18 control subjects completed the Barratt Impulsiveness Scale in addition to fMRI. Study 1 showed a significant group by ventral striatal BPND interaction effect on RSFC, reflecting a negative relationship between ventral striatal BPND and RSFC between the midbrain and striatum, orbitofrontal cortex and insula in methamphetamine-dependent participants, but a positive relationship in the control group. In Study 2, an interaction of the group with RSFC on impulsivity was observed. Methamphetamine-dependent users exhibited a positive relationship of midbrain RSFC to the left ventral striatum with cognitive impulsivity, whereas a negative relationship was observed in healthy controls. The results indicate that ventral striatal D2-type receptor signaling may affect the system-level activity within the mesocorticolimbic system, providing a functional link that may help explain high impulsivity in methamphetamine-dependent individuals.
Assuntos
Comportamento Impulsivo/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Estimulantes do Sistema Nervoso Central , Dopamina/metabolismo , Feminino , Humanos , Comportamento Impulsivo/fisiologia , Imageamento por Ressonância Magnética , Masculino , Metanfetamina/efeitos adversos , Metanfetamina/metabolismo , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D2/fisiologia , Estriado Ventral/efeitos dos fármacos , Estriado Ventral/fisiopatologiaRESUMO
Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [(18)F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.
Assuntos
Comportamento de Procura de Droga/fisiologia , Substância Cinzenta/patologia , Mesencéfalo/patologia , Metanfetamina , Receptores de Dopamina D2/metabolismo , Transtornos Relacionados ao Uso de Substâncias , Benzamidas/farmacocinética , Antagonistas de Dopamina/farmacocinética , Feminino , Fluordesoxiglucose F18/farmacocinética , Substância Cinzenta/efeitos dos fármacos , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/diagnóstico por imagem , Mesencéfalo/efeitos dos fármacos , Metanfetamina/farmacologia , Tomografia por Emissão de Pósitrons , Ligação Proteica/efeitos dos fármacos , Análise de Regressão , Transtornos Relacionados ao Uso de Substâncias/patologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Fatores de TempoRESUMO
BACKGROUND: Hypothyroidism induced by an autoimmune process is associated with neuropsychiatric symptoms and metabolic abnormalities in the brain. The aim of this study was to examine the relationship between autoimmune thyroiditis and regional brain function in hypothyroid patients. METHODS: Cerebral glucose metabolism, as an index of brain function, was assessed in regional whole-brain analyses using positron emission tomography (PET) and [18F]fluorodeoxyglucose in thirteen hypothyroid patients with autoimmune thyroiditis suffering from neuropsychiatric symptoms. The primary biological measures were radioactivity in pre-selected brain regions, relative to whole-brain radioactivity, as a surrogate index of glucose metabolism, and serum levels of thyroglobulin (TG) and thyroid peroxidase (TPO) antibodies as endocrine markers of autoimmune thyroiditis. RESULTS: Serum levels of anti-TG antibodies in hypothyroid patients were significantly correlated with glucose metabolism in the perigenual anterior cingulate cortex, a brain region previously shown to regulate affect and emotional homeostasis. CONCLUSION: Thyroid autoimmune processes may play an important role in the still poorly defined pathogenic correlates of disturbed function in brain regions critically involved in emotional processing in hypothyroid conditions.
Assuntos
Anticorpos/sangue , Encéfalo/metabolismo , Giro do Cíngulo/imunologia , Giro do Cíngulo/metabolismo , Tireoidite Autoimune/imunologia , Tireoidite Autoimune/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Giro do Cíngulo/diagnóstico por imagem , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/diagnóstico por imagem , Hipotireoidismo/metabolismo , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Tireoidite Autoimune/complicações , Tireoidite Autoimune/diagnóstico por imagemAssuntos
Substância Cinzenta/patologia , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Receptores Dopaminérgicos/metabolismo , Transtornos Relacionados ao Uso de Substâncias/patologia , Mapeamento Encefálico , Dopaminérgicos/toxicidade , Substância Cinzenta/efeitos dos fármacos , Humanos , Metanfetamina/toxicidadeRESUMO
Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse potential and can be neurotoxic. Although they have long been used effectively to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents, amphetamines are now being prescribed increasingly as maintenance therapy for ADHD and narcolepsy in adults, considerably extending the period of potential exposure. Effects of prolonged stimulant treatment have not been fully explored, and understanding such effects is a research priority. Because the pharmacokinetics of amphetamines differ between children and adults, reevaluation of the potential for adverse effects of chronic treatment of adults is essential. Despite information on the effects of stimulants in laboratory animals, profound species differences in susceptibility to stimulant-induced neurotoxicity underscore the need for systematic studies of prolonged human exposure. Early amphetamine treatment has been linked to slowing in height and weight growth in some children. Because the number of prescriptions for amphetamines has increased several fold over the past decade, an amphetamine-containing formulation is the most commonly prescribed stimulant in North America, and it is noteworthy that amphetamines are also the most abused prescription medications. Although early treatment does not increase risk for substance abuse, few studies have tracked the compliance and usage profiles of individuals who began amphetamine treatment as adults. Overall, there is concern about risk for slowed growth in young patients who are dosed continuously, and for substance abuse in patients first medicated in late adolescence or adulthood. Although most adult patients also use amphetamines effectively and safely, occasional case reports indicate that prescription use can produce marked psychological adverse events, including stimulant-induced psychosis. Assessments of central toxicity and adverse psychological effects during late adulthood and senescence of adults who receive prolonged courses of amphetamine treatment are warranted. Finally, identification of the biological factors that confer risk and those that offer protection is also needed to better specify the parameters of safe, long-term, therapeutic administration of amphetamines to adults.
Assuntos
Anfetamina/efeitos adversos , Comportamento/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/efeitos adversos , Síndromes Neurotóxicas/etiologia , Transtornos Relacionados ao Uso de Substâncias/etiologia , Anfetamina/história , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/história , Prescrições de Medicamentos/estatística & dados numéricos , História do Século XX , História do Século XXI , Humanos , Narcolepsia/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/classificaçãoRESUMO
Brief intensive cognitive-behavioral therapy (CBT) using exposure and response prevention significantly improves obsessive-compulsive disorder (OCD) symptoms in as little as 4 weeks. However, it has been thought that much longer treatment was needed to produce the changes in brain function seen in neuroimaging studies of OCD. We sought to elucidate the brain mediation of response to brief intensive CBT for OCD and determine whether this treatment could induce functional brain changes previously seen after longer trials of pharmacotherapy or standard CBT. [(18)F]-fluorodeoxyglucose positron emission tomography brain scans were obtained on 10 OCD patients before and after 4 weeks of intensive individual CBT. Twelve normal controls were scanned twice, several weeks apart, without treatment. Regional glucose metabolic changes were compared between groups. OCD symptoms, depression, anxiety and overall functioning improved robustly with treatment. Significant changes in normalized regional glucose metabolism were seen after brief intensive CBT (P=0.04). Compared to controls, OCD patients showed significant bilateral decreases in normalized thalamic metabolism with intensive CBT but had a significant increase in right dorsal anterior cingulate cortex activity that correlated strongly with the degree of improvement in OCD symptoms (P=0.02). The rapid response of OCD to intensive CBT is mediated by a distinct pattern of changes in regional brain function. Reduction of thalamic activity may be a final common pathway for improvement in OCD, but response to intensive CBT may require activation of dorsal anterior cingulate cortex, a region involved in reappraisal and suppression of negative emotions.
Assuntos
Encéfalo/metabolismo , Terapia Cognitivo-Comportamental/métodos , Glucose/metabolismo , Transtorno Obsessivo-Compulsivo/patologia , Transtorno Obsessivo-Compulsivo/terapia , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Feminino , Fluordesoxiglucose F18/metabolismo , Lateralidade Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Adulto JovemRESUMO
Changes in brain function during the initial weeks of abstinence from chronic methamphetamine abuse may substantially affect clinical outcome, but are not well understood. We used positron emission tomography with [F-18]fluorodeoxyglucose (FDG) to quantify regional cerebral glucose metabolism, an index of brain function, during performance of a vigilance task. A total of 10 methamphetamine-dependent subjects were tested after 5-9 days of abstinence, and after 4 additional weeks of supervised abstinence. A total of 12 healthy control subjects were tested at corresponding times. Global glucose metabolism increased between tests (P=0.01), more in methamphetamine-dependent (10.9%, P=0.02) than control subjects (1.9%, NS). Glucose metabolism did not change in subcortical regions of methamphetamine-dependent subjects, but increased in neocortex, with maximal increase (>20%) in parietal regions. Changes in reaction time and self-reports of negative affect varied more in methamphetamine-dependent than in control subjects, and correlated both with the increase in parietal glucose metabolism, and decrease in relative activity (after scaling to the global mean) in some regions. A robust relationship between change in self-reports of depressive symptoms and relative activity in the ventral striatum may have great relevance to treatment success because of the role of this region in drug abuse-related behaviors. Shifts in cortical-subcortical metabolic balance either reflect new processes that occur during early abstinence, or the unmasking of effects of chronic methamphetamine abuse that are obscured by suppression of cortical glucose metabolism that continues for at least 5-9 days after cessation of methamphetamine self-administration.
Assuntos
Córtex Cerebral/metabolismo , Glucose/metabolismo , Metanfetamina/efeitos adversos , Síndrome de Abstinência a Substâncias/metabolismo , Estimulação Acústica/métodos , Adulto , Atenção/fisiologia , Mapeamento Encefálico , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Depressão/etiologia , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Tempo de Reação/fisiologia , Síndrome de Abstinência a Substâncias/complicações , Síndrome de Abstinência a Substâncias/diagnóstico por imagem , Síndrome de Abstinência a Substâncias/patologia , Análise e Desempenho de TarefasRESUMO
Specific sigma binding sites have been identified in the mammalian brain and lymphoid tissue. In this study, certain gonadal and adrenal steroids, particularly progesterone, were found to inhibit sigma receptor binding in homogenates of brain and spleen. The findings suggest that steroids are naturally occurring ligands for sigma receptors and raise the possibility that these sites mediate some aspects of steroid-induced mental disturbances and alterations in immune functions.
Assuntos
Glândulas Endócrinas/fisiologia , Imunidade , Fenômenos Fisiológicos do Sistema Nervoso , Receptores Opioides/metabolismo , Esteroides/metabolismo , Animais , Encéfalo/metabolismo , Cobaias , Haloperidol/metabolismo , Masculino , Fenazocina/análogos & derivados , Fenazocina/metabolismo , Receptores sigma , Baço/metabolismoAssuntos
Leptina/análogos & derivados , Leptina/deficiência , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Adulto , Benzamidas , Estudos de Casos e Controles , Corpo Estriado/metabolismo , Feminino , Radioisótopos de Flúor , Terapia de Reposição Hormonal/métodos , Humanos , Leptina/administração & dosagem , Leptina/genética , Leptina/uso terapêutico , Masculino , Mutação de Sentido Incorreto , Ensaio Radioligante/métodosRESUMO
The nonmedical use of amphetamine-type stimulants is a worldwide problem, with substantial medical and social consequences. Nonetheless, the identification of a pharmacological treatment for amphetamine use disorder remains elusive. Stimulant users exhibit neurochemical evidence of dopamine-system dysfunction as well as impulsive behaviors that may interfere with the success of treatments for their addiction. This review focuses on the potential role of dopaminergic neurotransmission in impulsivity, both in healthy individuals and chronic stimulant users who meet criteria for methamphetamine dependence. Presented are findings related to the potential contributions of signaling through dopamine D1- and D2-type receptors to self-control impulsivity in methamphetamine- dependent users. The information available points to signaling through striatal D2-type dopamine receptors as a potential therapeutic target for stimulant use disorders, but medications that target D2-type dopamine receptors have not been successful in treating stimulant-use disorders, possibly because D2-type receptors are downregulated. Other means to augment D2-type receptor signaling are therefore under consideration, and one promising approach is the addition of exercise training as an adjunct to behavioral treatment for addiction.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Comportamento Impulsivo/efeitos dos fármacos , Metanfetamina/efeitos adversos , Estimulantes do Sistema Nervoso Central , Corpo Estriado/metabolismo , Dopamina/metabolismo , Humanos , Receptores de Dopamina D2/metabolismo , Transmissão SinápticaRESUMO
This data descriptor outlines a shared neuroimaging dataset from the UCLA Consortium for Neuropsychiatric Phenomics, which focused on understanding the dimensional structure of memory and cognitive control (response inhibition) functions in both healthy individuals (130 subjects) and individuals with neuropsychiatric disorders including schizophrenia (50 subjects), bipolar disorder (49 subjects), and attention deficit/hyperactivity disorder (43 subjects). The dataset includes an extensive set of task-based fMRI assessments, resting fMRI, structural MRI, and high angular resolution diffusion MRI. The dataset is shared through the OpenfMRI project, and is formatted according to the Brain Imaging Data Structure (BIDS) standard.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno Bipolar/fisiopatologia , Cognição/fisiologia , Inibição Psicológica , Memória/fisiologia , Esquizofrenia/fisiopatologia , Adulto , Feminino , Neuroimagem Funcional , Voluntários Saudáveis , Humanos , Disseminação de Informação , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise e Desempenho de Tarefas , Adulto JovemRESUMO
We examined the effects of cocaine hydrochloride (40 mg intravenously) on regional cerebral metabolic rates for glucose and on subjective self-reports of eight polydrug abusers in a double-blind, placebo-controlled, crossover study. The regional cerebral metabolic rate for glucose was measured by the [fluorine 18]-fluorodeoxyglucose method, using positron emission tomography. With eyes covered, subjects listened to a tape that presented white noise, "beep" prompts, and questions about subjective effects of cocaine or saline. Cocaine produced euphoria and reduced glucose utilization globally (mean reduction, 14%). Twenty-six of 29 brain regions (all neocortical areas, basal ganglia, portions of the hippocampal formation, thalamus, and midbrain) showed significant decrements (5% to 26%) in the regional cerebral metabolic rate for glucose. No significant effects of cocaine were observed in the pons, the cerebellar cortex, or the vermis. Right-greater-than-left hemispheric asymmetry of regional cerebral metabolic rates for glucose occurred in the lateral thalamus. The findings demonstrate that reduced cerebral metabolism is associated with cocaine-induced euphoria.
Assuntos
Encéfalo/metabolismo , Cocaína/farmacologia , Glucose/metabolismo , Transtornos Relacionados ao Uso de Substâncias , Adulto , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Desoxiglucose/análogos & derivados , Desoxiglucose/metabolismo , Método Duplo-Cego , Euforia , Fluordesoxiglucose F18 , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Placebos , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia , Tomografia Computadorizada de EmissãoRESUMO
Morphine sulfate effects (30 mg, intramuscularly) on cerebral glucose utilization and subjective self-reports were examined in 12 polydrug abusers by positron emission tomography and [fluorine 18]fluorodeoxyglucose in a double-blind placebo-controlled crossover study. During testing, subjects sat with eyes covered, listening to white noise and "beep" prompts. Morphine significantly reduced glucose utilization by 10% in whole brain and by about 5% to 15% in telencephalic areas and the cerebellar cortex, assuming no contribution of hypercapnia. When the contribution of PaCO2 (45 minutes after morphine was administered) was partialled out, significant morphine-induced reductions persisted in whole brain and six cortical areas. Irrespective of morphine, left-greater-than-right asymmetry occurred in the temporal cortex, and an interaction between hemisphere and drug was noted in the postcentral gyrus. In most cases, effects on glucose utilization were not significantly related to measures of euphoria.
Assuntos
Encéfalo/efeitos dos fármacos , Glucose/metabolismo , Morfina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ensaios Clínicos como Assunto , Desoxiglucose/análogos & derivados , Método Duplo-Cego , Euforia , Fluordesoxiglucose F18 , Lateralidade Funcional , Frequência Cardíaca/efeitos dos fármacos , Humanos , Injeções Intramusculares , Morfina/administração & dosagem , Placebos , Pupila/efeitos dos fármacos , Respiração/efeitos dos fármacos , Telencéfalo/efeitos dos fármacos , Telencéfalo/metabolismo , Tomografia Computadorizada de EmissãoRESUMO
Drugs such as phencyclidine (PCP) that interact with PCP and sigma binding sites can produce psychotomimetic effects that resemble some symptoms of schizophrenia. Therefore, it has been suggested that PCP and sigma receptors may be important in the clinical manifestations of schizophrenia. Assays of these two binding sites in human postmortem brains showed consistent significant reductions in the density of sigma, but not PCP sites, in schizophrenics as compared with age-matched and postmortem interval-matched normal and suicide controls. Reductions in the density of sigma binding sites in schizophrenia were most prominent in temporal cerebral cortex, and were accompanied by a small increase in affinity for the ligand [3H]haloperidol. These data provide the first evidence for alterations in sigma binding sites in schizophrenia, and suggest that selective sigma ligands may be useful in the treatment of the disorder.
Assuntos
Encéfalo/patologia , Receptores de Neurotransmissores/análise , Receptores Opioides/análise , Esquizofrenia/patologia , Doença Crônica , Humanos , Ensaio Radioligante , Receptores da Fenciclidina , Receptores sigma , Esquizofrenia Paranoide/patologiaRESUMO
The specific binding of (3H)kainic acid (KA) to high- and low-affinity receptor sites was assayed in postmortem samples from the brains of patients affected with Huntington's disease (HD) and age-matched controls. Treatment of rat brain with conditions that closely mimic the temperature gradient occurring in postmortem human brain only slightly but not significantly decreased receptor binding by 12 hr after death. In HD brains, total specific binding of (3H)KA was reduced in the caudate nucleus by 51%, putamen by 77%, and frontal cortex by 47%. Specific binding to the high-affinity site was virtually undetectable in the caudate nucleus and was reduced by 90% in the putamen from HD brains. No significant alterations in specific binding of (3H)KA were noted in the insular or temporal cortex, hippocampus, or cerebellum. Thus, losses of KA receptor binding were mainly localized to those regions of the HD brain that are most severely affected by neuronal degeneration, and the high-affinity receptor site appeared more affected.
Assuntos
Química Encefálica , Doença de Huntington/metabolismo , Ácido Caínico/metabolismo , Pirrolidinas/metabolismo , Receptores de Droga/análise , Adulto , Animais , Sítios de Ligação , Núcleo Caudado/análise , Feminino , Lobo Frontal/análise , Humanos , Masculino , Pessoa de Meia-Idade , Mudanças Depois da Morte , Putamen/análise , RatosRESUMO
Rats received unilateral injections of ibotenic acid (12 micrograms) or vehicle in the ventromedial globus pallidus to lesion the primary source of cortical cholinergic innervation. At 3 or 28-32 days postinjection, the regional cerebral metabolic rate for glucose (rCMRglu) was measured by the 2-deoxy-D-[14C]glucose technique in nine cortical areas, the anterior thalamus, and the dorsal hippocampus. Effects of oxotremorine (0.1 mg/kg i.p.) on rCMRglu in these areas were assessed in ibotenic acid-lesioned and sham-treated rats. Significant effects of ibotenic acid injections and hemispheric asymmetries in rCMRglu were observed in all cortical areas (p less than or equal to 0.05), but not in the anterior thalamus or hippocampus. Cortical rCMRglu generally was lower in the lesioned hemisphere 3 days after ibotenic acid injections, but not after sham treatments. Hemispheric asymmetries were not apparent 28-32 days after pallidal lesions. Oxotremorine produced significant effects in the frontoparietal cortex and anterior thalamic nuclei. In the frontoparietal cortex, rCMRglu was 32% lower in the ibotenate-lesioned hemisphere as compared with the contralateral hemisphere. Oxotremorine did not eliminate hemispheric asymmetry, but increased rCMRglu in the lesioned frontoparietal cortex by 38%. Results support the views that cortical metabolic decrements in Alzheimer's disease are due in part to loss of subcortical cholinergic innervation and that muscarinic agonists may partially reverse these decrements.