RESUMO
BACKGROUND: The superior thyroid artery (STA) is one of the main arteries that provide blood supply to the thyroid gland. It has a plethora of anatomical variations, and knowledge of its anatomy is necessary in procedures in this area. The aim of this review is to summarize and describe human studies (cadaveric and angiographic) that investigate the anatomical variations related to the STA. MATERIAL AND METHODS: A systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. A literature search in PubMed, and Embase databases was carried out. Original studies that investigated the origin of the STA and reported data on the variant arterial anatomy were considered, including only cadaveric and angiographic studies. RESULTS: A total of 34 studies (4048 heminecks in total; heminecks in each study: min: 25-max: 1280) were finally included. All studies provide details about sex [men/women ratio median (IQR): 2(1-5)] but none about age and 10 (29%) about nationality. STA morphological characteristics described in the included studies are origin, length, number of branches, distance from the carotid bifurcation and the vessel's diameter. CONCLUSIONS: The STA's anatomical features are subject to a non-negligible degree of variability. Our results should improve the awareness of anatomical variations of the STA, and eventually have an impact on the interventions regarding the visceral compartment of the neck in clinical practice.
Assuntos
Artérias , Glândula Tireoide , Masculino , Humanos , Feminino , Criança , Glândula Tireoide/anatomia & histologia , Glândula Tireoide/irrigação sanguínea , Artérias/diagnóstico por imagem , Artérias/anatomia & histologia , Pescoço , CadáverRESUMO
Clorgyline is an irreversible inhibitor of monoamine oxidase (MAO A) which has been labeled with carbon-11 (C-11) and used to measure human brain MAO A with positron emission tomography (PET). In this study we compared [11C]clorgyline and deuterium-substituted [11C]clorgyline ([11C]clorgyline-D2) to better understand the molecular link between [11C]clorgyline binding and MAO A. In PET studies of five normal healthy volunteers scanned with [11C]clorgyline and [11C]clorgyline-D2 2 h apart, deuterium substitution generally produced the expected reductions in the brain uptake of [11C]clorgyline. However, the reduction was not uniform with the C-11 binding in white matter being significantly less sensitive to deuterium substitution than other brain regions. The percentages of the total binding attributable to MAO A is largest for the thalamus and smallest for the white matter and this is clearly seen in PET images with [11C]clorgyline-D2. Thus deuterium-substituted [11C]clorgyline selectively reduces the MAO A binding component of clorgyline in the human brain revealing non-MAO A binding which is most apparent in the white matter. The characterization of the non-MAO A binding component of this widely used MAO A inhibitor merits further investigation.
Assuntos
Encéfalo/metabolismo , Clorgilina/metabolismo , Inibidores da Monoaminoxidase/metabolismo , Monoaminoxidase/metabolismo , Adulto , Algoritmos , Encéfalo/diagnóstico por imagem , Encéfalo/enzimologia , Humanos , Cinética , Masculino , Ligação Proteica , Receptores de Dopamina D2/metabolismo , Tomografia Computadorizada de EmissãoRESUMO
OBJECTIVE: The role of dopamine in the addictive process (loss of control and compulsive drug intake) is poorly understood. A consistent finding in drug-addicted subjects is a lower level of dopamine D2 receptors. In cocaine abusers, low levels of D2 receptors are associated with a lower level of metabolism in the orbitofrontal cortex. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. This study explored whether a similar association occurs in methamphetamine abusers. METHOD: Fifteen methamphetamine abusers and 20 non-drug-abusing comparison subjects were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors and with [18F]fluorodeoxyglucose to assess regional brain glucose metabolism, a marker of brain function. RESULTS: Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a difference of 16% in the caudate and 10% in the putamen). D2 receptor availability was associated with metabolic rate in the orbitofrontal cortex in abusers and in comparison subjects. CONCLUSIONS: Lower levels of dopamine D2 receptor availability have been previously reported in cocaine abusers, alcoholics, and heroine abusers. This study extends this finding to methamphetamine abusers. The association between level of dopamine D2 receptors and metabolism in the orbitofrontal cortex in methamphetamine abusers, which replicates previous findings in cocaine abusers, suggests that D2 receptor-mediated dysregulation of the orbitofrontal cortex could underlie a common mechanism for loss of control and compulsive drug intake in drug-addicted subjects.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Metabolismo Energético/efeitos dos fármacos , Lobo Frontal/efeitos dos fármacos , Metanfetamina/efeitos adversos , Receptores de Dopamina D2/efeitos dos fármacos , Tomografia Computadorizada de Emissão , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Comportamento Compulsivo/diagnóstico por imagem , Comportamento Compulsivo/fisiopatologia , Metabolismo Energético/fisiologia , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos , Masculino , Metanfetamina/administração & dosagem , Receptores de Dopamina D2/fisiologia , Fatores de RiscoRESUMO
[11C]Clorgyline selectively binds to MAO A in the human brain. This contrasts with a recent report that [11C]clorgyline (in contrast to other labeled MAO A inhibitors) is not retained in the rhesus monkey brain [4]. To explore this difference, we compared [11C]clorgyline in the baboon brain before and after clorgyline pretreatment and we also synthesized deuterium substituted [11C]clorgyline (and its nor-precursor) for comparison. [11C]Clorgyline was not retained in the baboon brain nor was it influenced by clorgyline pretreatment or by deuterium substitution, contrasting to results in humans. This suggests a species difference in the susceptibility of MAO A to inhibition by clorgyline and represents an unusual example of where the behavior of a radiotracer in the baboon brain does not predict its behavior in the human brain.
Assuntos
Encéfalo/metabolismo , Clorgilina/farmacocinética , Inibidores da Monoaminoxidase/farmacocinética , Monoaminoxidase/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/enzimologia , Radioisótopos de Carbono/farmacocinética , Clorgilina/análogos & derivados , Deutério , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Indicadores e Reagentes , Marcação por Isótopo , Papio , Compostos Radiofarmacêuticos/síntese química , Especificidade da Espécie , Tomografia Computadorizada de EmissãoRESUMO
In this study, we investigated whether treatment with L-deprenyl, a selective monoamine oxidase B (MAO B) inhibitor, also inhibits MAO A or the dopamine transporter in the human brain. Six normal volunteers (age 46+/-6 yrs) had two PET sessions, one at baseline and one following L-deprenyl (10 mg/day) for 1 week. Each session included one scan with [11C]clorgyline (to assess MAO A) and one scan 2 hours later with [11C]cocaine (to assess dopamine transporter availability). A 3-compartment model was used to compare the plasma-to-brain transfer constant, K1 (a function of blood flow) and lambdak3 (a kinetic term proportional to brain MAO A) before and after treatment. Dopamine transporter availability was measured as the ratio of distribution volumes of the striatum to cerebellum (DVR) which is equal to Bmax/KD +1. L-Deprenyl treatment for 1 week did not affect either brain MAO A activity or dopamine transporter availability. There was a non-significant trend for an increase in K1 after L-deprenyl. These results confirm that L-deprenyl after one week of treatment at doses typically used clinically is selective for MAO B and that it does not produce a measurable affect on the dopamine transporter, suggesting that MAO A inhibition and dopamine transporter blockade do not contribute to its pharmacological effects.
Assuntos
Encéfalo/efeitos dos fármacos , Proteínas de Transporte/antagonistas & inibidores , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Inibidores da Monoaminoxidase/farmacologia , Proteínas do Tecido Nervoso , Selegilina/farmacologia , Adulto , Clorgilina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The cerebral mechanisms underlying the behaviours that lead to pathological overeating and obesity are poorly understood. Dopamine, a neurotransmitter that modulates rewarding properties of food, is likely to be involved. To test the hypothesis that obese individuals have abnormalities in brain dopamine activity we measured the availability of dopamine D2 receptors in brain. METHODS: Brain dopamine D2 receptor availability was measured with positron emission tomography (PET) and [C-11]raclopride (a radioligand for the dopamine D2 receptor). Bmax/Kd (ratio of the distribution volumes in striatum to that in cerebellum minus 1) was used as a measure of dopamine D2 receptor availability. Brain glucose metabolism was also assessed with 2-deoxy-2[18F]fluoro-D-glucose (FDG). FINDINGS: Striatal dopamine D2 receptor availability was significantly lower in the ten obese individuals (2.47 [SD 0.36]) than in controls (2.99 [0.41]; p < or = 0.0075). In the obese individuals body mass index (BMI) correlated negatively with the measures of D2 receptors (r=0.84; p < or = 0.002); the individuals with the lowest D2 values had the largest BMI. By contrast, neither whole brain nor striatal metabolism differed between obese individuals and controls, indicating that striatal reductions in D2 receptors were not due to a systematic reduction in radiotracer delivery. INTERPRETATION: The availability of dopamine D2 receptor was decreased in obese individuals in proportion to their BMI. Dopamine modulates motivation and reward circuits and hence dopamine deficiency in obese individuals may perpetuate pathological eating as a means to compensate for decreased activation of these circuits. Strategies aimed at improving dopamine function may be beneficial in the treatment of obese individuals.
Assuntos
Cerebelo/metabolismo , Corpo Estriado/metabolismo , Obesidade/metabolismo , Receptores de Dopamina D2/metabolismo , Adulto , Análise de Variância , Mapeamento Encefálico , Estudos de Casos e Controles , Feminino , Glucose/metabolismo , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de EmissãoRESUMO
OBJECTIVE: The authors' goal was to replicate a previous finding that smokers have lower brain monoamine oxidase B (MAO-B) levels than comparison nonsmoking subjects and to determine if levels recover after overnight cigarette abstinence. METHOD: Brain MAO-B levels were measured by means of positron emission tomography in six smokers who were scanned twice: 11.3 hours (baseline) and 10 minutes after smoking one cigarette. RESULTS: Average MAO-B levels in smokers in the present study were similar to those found in the previous study and averaged 39% (SD=17) lower than those found in a comparison group of nonsmokers. Brain MAO-B levels did not differ between baseline levels and 10 minutes after smoking. CONCLUSIONS: This study reinforces the need to investigate whether MAO-B inhibition may account for some of the behavioral and epidemiological features of smoking.
Assuntos
Encéfalo/enzimologia , Monoaminoxidase/metabolismo , Fumar/metabolismo , Tomografia Computadorizada de Emissão/estatística & dados numéricos , Adulto , Idoso , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Inibidores Enzimáticos/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monoaminoxidase/sangue , Fumar/sangue , Fumar/psicologia , Distribuição TecidualRESUMO
Though it has been postulated that cortical brain regions participate in the regulation of heart rate, their involvement is poorly understood. Using PET and [18] FDG (to measure regional brain glucose metabolism, which serves as an index of brain function) we compared the regional brain metabolic activity between healthy subjects with bradycardia (<60 beats per minute) with those with normal heart rates in the 75-100 beats per minute range. Statistical Parametric Mapping (SPM) analyses revealed significant differences between the groups predominantly localized to the temporal insula. This finding was corroborated by a separate analysis that measured the metabolic activity for each subject in preselected regions located in the temporal insula. Subjects with bradycardia had significantly higher metabolic activity in the right (p < 0.0001) and in the left temporal insula (p < 0.015) than those with normal heart rates. Moreover, resting heart rates were negatively correlated with metabolism in the right (r = -0.77, p < 0.0001) and in the left temporal insula (r = -0.44, p < 0.05). These results corroborate the importance of the temporal insula in the regulation of resting heart rate in humans. The temporal insula is interconnected with limbic brain region and autonomic centers and suggests that this may be a mechanism by which emotional responses regulate heart rate.
Assuntos
Bradicardia/metabolismo , Encéfalo/metabolismo , Glucose/metabolismo , Adulto , Fluordesoxiglucose F18 , Frequência Cardíaca , Humanos , Masculino , Tomografia Computadorizada de EmissãoRESUMO
The route of administration influences the reinforcing effects of cocaine. Here we assessed whether there were differences in the efficacy of cocaine to block the dopamine transporters (major target for cocaine's reinforcing effects), as a function of route of administration. Positron emission tomography and [11C]cocaine, a dopamine transporter radioligand, were used to compare the levels of dopamine transporter blockade induced by intravenous, smoked and intranasal cocaine in 32 current cocaine abusers. In parallel, the temporal course for the self-reports of "high" were obtained. Cocaine significantly blocked dopamine transporters. The levels of blockade were comparable across all routes of administration and a dose effect was observed for intravenous and intranasal cocaine but not for smoked cocaine. For equivalent levels of cocaine in plasma and DAT blockade, smoked cocaine induced significantly greater self reports of "high" than intranasal cocaine and showed a trend for a greater effect than intravenous cocaine. The time to reach peak subjective was significantly faster for smoked (1.4+/-0.5 min) than for intravenous cocaine (3.1+/-0.9 min), which was faster than intranasal cocaine (14.6+/-8 min). Differences in the reinforcing effects of cocaine as a function of the route of administration are not due to differences in the efficacy of cocaine to block the dopamine transporters. The faster time course for the subjective effects for smoked than intravenous and for intravenous than for intranasal cocaine highlights the importance of the speed of cocaine's delivery into the brain on its reinforcing effects.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/fisiologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Administração por Inalação , Administração Intranasal , Proteínas da Membrana Plasmática de Transporte de Dopamina , Humanos , Injeções IntravenosasRESUMO
This paper presents outcome data from our initial 150 patients who had received all or part of their radiation dose for the treatment of adenocarcinoma of the prostate using permanent radioactive seed implantation. Median follow-up for this group is now three years. Fifty-six patients had tumors with gleason scores of 7 or greater, and 94 had gleason scores of 6 or less. The average age was 67 (range 42 to 79). Ninety-five percent have maintained biochemical control of their disease (PSA level of 1.0 or less) since the time of implant. Questionnaires were sent to all patients to assess quality of life issues. Fifty-eight percent have maintained potency. Ninety-eight percent of those surveyed said they would recommend this treatment to other men with prostate cancer. Our results support the findings of other published series. Ultrasound-guided transperineal brachytherapy is a well-tolerated procedure with excellent cancer control rates and should be considered as a treatment option in men with localized prostate cancer.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/radioterapia , Braquiterapia/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Ultrassonografia de Intervenção/métodos , Adenocarcinoma/sangue , Adenocarcinoma/psicologia , Adulto , Idoso , Braquiterapia/psicologia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/psicologia , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento , Ultrassonografia de Intervenção/psicologiaRESUMO
UNLABELLED: In vivo microdialysis studies have shown that exercise increases the concentration of dopamine (DA) in the striatum of the rat brain. It has also been shown that PET with [11C]raclopride can be used to assess changes in brain DA induced by drugs and by performance tasks such as playing a video game. The purpose of this study was to evaluate the effects of exercise (treadmill running) on striatal DA release in the human brain. METHODS: Twelve healthy volunteers (5 women, 7 men; mean age, 32 +/- 5 y; age range, 25-40 y) with a history of regular exercise received 2 PET scans with [11C]raclopride on 2 separate days, 1 at baseline and 1 at 5-10 min after running on a treadmill for 30 min. The speed and inclination of the treadmill were increased gradually to reach a maximal speed of 9.7 km/h (6 mph) and a maximal inclination of 10degrees. Data were acquired on a Siemens HR+ scanner in 3-dimensional mode for 60 min. Heart rates and electrocardiograms were monitored. DA D2 receptor availability was measured using the ratio of the distribution volume in the putamen to that in the cerebellum, which is a function of the number of available binding sites/dissociation constant. RESULTS: The subjects ran at an average speed of 8.7 +/- 0.5 km/h (5.4 +/- 0.3 mph) and at an inclination of 3.3degrees +/- 2degrees. The maximum effort of running was maintained for 10-15 min. The heart rates of the subjects were increased by 143% +/- 47%. DA D2 receptor availability in the putamen after treadmill running (4.22 +/- 0.34) was no different from that of baseline (4.17 +/- 0.29; P < 0.6). CONCLUSION: No significant changes in synaptic DA concentration were detected, although the subjects exercised vigorously for 30 min.
Assuntos
Radioisótopos de Carbono/farmacocinética , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/fisiologia , Dopamina/metabolismo , Exercício Físico/fisiologia , Esforço Físico/fisiologia , Racloprida/farmacocinética , Receptores de Dopamina D2/metabolismo , Adulto , Animais , Teste de Esforço , Feminino , Humanos , Corrida Moderada , Masculino , Ratos , Receptores de Dopamina D2/análise , Valores de Referência , Tomografia Computadorizada de EmissãoRESUMO
BACKGROUND: Ethanol has a broad range of actions on many neurotransmitter systems. The depressant actions of ethanol in the brain are related in part to facilitation of gamma-aminobutyric acid (GABA) neurotransmission via its interaction with the benzodiazepine/GABA receptor complex. The purpose of this study was to evaluate the effects of ethanol on regional brain metabolism in 10 healthy right-handed men. The results were compared with those we previously published in a different group of 16 normal male subjects who received intravenous lorazepam, a benzodiazepine drug that also enhances GABA neurotransmission. METHODS: The subjects were scanned with positron emission tomography and [F-18] fluorodeoxyglucose twice: 40 min after the end of placebo (diet soda) or ethanol (0.75 g/kg) oral administration. Image data sets were analyzed by using both the region of interest and the statistical parametric mapping (SPM) approach. SPM was used to generate a difference image between baseline and ethanol, which we compared to the difference image between baseline and lorazepam (30 microg/kg). RESULTS: Ethanol significantly increased self-reports of "high" (p < or = 0.0001), dizziness (p < or = 0.004), and intoxication (p < or = 0.0001). Ethanol significantly decreased whole brain (-25 +/- 6%, p < or = 0.0001) and regional metabolism. Normalization of the regional measures by whole brain metabolism (relative measures) showed that ethanol decreased relative metabolic activity in occipital cortex (-4.9 +/- 4.1%, p < or = 0.006), whereas it increased relative metabolic act in left temporal cortex (+3.5 +/- 2.9%, p < or = 0.006) and left basal ganglia (+9 +/- 6.3%, p < or = 0.0009). SPM analyses revealed the same pattern of responses as the relative measures, showing decreases in occipital cortex and increases in left temporal cortex. Comparison of the relative measures and the SPM analyses obtained with lorazepam data revealed a similar pattern of effects, with relative decreases in occipital cortex (-7.8 +/- 4.8%) and relative increases in left temporal cortex (+3.8 +/- 5.7%). Lorazepam, but not ethanol, also decreased thalamic metabolism (-11.2 +/- 7.2%). CONCLUSIONS: These results support similar though not identical mechanisms for the effects of alcohol and benzodiazepines on brain glucose metabolism. The fact that lorazepam, but not alcohol, reduced thalamic metabolism, an effect associated with sleepiness, could explain the higher sedative effects of lorazepam than of alcohol.
Assuntos
Intoxicação Alcoólica/metabolismo , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Adulto , Afeto/efeitos dos fármacos , Intoxicação Alcoólica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Mapeamento Encefálico , Moduladores GABAérgicos/farmacologia , Humanos , Lorazepam/farmacologia , Masculino , Pessoa de Meia-Idade , Placebos , Tomografia Computadorizada de EmissãoRESUMO
UNLABELLED: Cocaine and alcohol are frequently used simultaneously and this combination is associated with enhanced toxicity. We recently showed that active cocaine abusers have a markedly enhanced sensitivity to benzodiazepines. Because both benzodiazepines and alcohol facilitate GABAergic neurotransmission we questioned whether cocaine abusers would also have an enhanced sensitivity to alcohol that could contribute to the toxicity. In this study we compared the effects of alcohol (0.75 g/kg) on regional brain glucose metabolism between cocaine abusers (n = 9) and controls (n = 10) using PET and FDG. Alcohol significantly decreased whole brain metabolism and this effect was greater in controls (26+/-6%) than in abusers (17+/-10%) even though they had equivalent levels of alcohol in plasma. Analysis of the regional measures showed that cocaine abusers had a blunted response to alcohol in limbic regions, cingulate gyrus, medial frontal and orbitofrontal cortices. CONCLUSIONS: The blunted response to alcohol in cocaine abusers contrasts with their enhanced sensitivity to benzodiazepines suggesting that targets other than GABA-benzodiazepine receptors are involved in the blunted sensitivity to alcohol and that the toxicity from combined cocaine-alcohol use is not due to an enhanced sensitivity to alcohol in cocaine abusers. The blunted response to alcohol in limbic regions and in cortical regions connected to limbic areas could result from a decreased sensitivity of reward circuits in cocaine abusers.
Assuntos
Intoxicação Alcoólica/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Glucose/metabolismo , Sistema Límbico/metabolismo , Adulto , Intoxicação Alcoólica/diagnóstico por imagem , Intoxicação Alcoólica/fisiopatologia , Transtornos Relacionados ao Uso de Cocaína/diagnóstico por imagem , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Fluordesoxiglucose F18/metabolismo , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/fisiopatologia , Tomografia Computadorizada de EmissãoRESUMO
OBJECTIVE: Despite the well-documented loss of brain dopamine activity with age, little is known about its functional consequences in healthy individuals. This study investigates the relationship between measures of brain dopamine D(2) receptors (molecules that transmit dopamine signals) and regional brain glucose metabolism (a marker of brain function) in healthy individuals. METHOD: Thirty-seven healthy volunteers aged 24-86 years underwent positron emission tomography scans after injection of [(11)C]raclopride to assess dopamine D(2) receptors and [(18)]fluorodeoxyglucose to assess regional brain glucose metabolism. Two methods used to assess the correlations between metabolism and dopamine D(2) receptors-pixel-by-pixel correlations and correlations in preselected regions of interest-were then compared. RESULTS: D(2) receptors as well as frontal and cingulate metabolism declined with age. Regardless of the method used, significant correlations between metabolism and D(2) receptors were found in the frontal cortex (Brodmann's areas 6, 7, 8, 9, 10, 11, 44, 45, 47), anterior cingulate gyrus (areas 24, 32), temporal cortex (area 21), and caudate. These correlations remained significant after removing age effects (partial correlation). CONCLUSIONS: These results provide the first link between age-related declines in brain dopamine activity and frontal and cingulate metabolism, which supports the need to investigate the therapeutic utility of interventions that enhance dopamine function in the elderly. The fact that correlations remained significant after removing age effects suggests that dopamine may influence frontal, cingulate, and temporal metabolism regardless of age.
Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Dopamina/metabolismo , Lobo Frontal/metabolismo , Glucose/metabolismo , Giro do Cíngulo/metabolismo , Adulto , Fatores Etários , Idoso , Encéfalo/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Feminino , Fluordesoxiglucose F18 , Lobo Frontal/diagnóstico por imagem , Giro do Cíngulo/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Racloprida , Receptores de Dopamina D2/análise , Tomografia Computadorizada de EmissãoRESUMO
Increases in dopamine concentration in limbic brain regions have been postulated to underlie the reinforcing effects of psychostimulant drugs in laboratory animals. However, neither the qualitative nor the quantitative relationship between drug-induced increases in brain dopamine and the reinforcing effects of psychostimulant drugs have been investigated in humans. Positron emission tomograph and [(11)C]raclopride, a dopamine D(2) receptor radioligand that competes with endogenous dopamine for occupancy of the D(2) receptors, were used to measure changes in brain dopamine after different doses of i.v. methylphenidate in 14 healthy controls. In parallel, measures for self-reports of drug effects were obtained to assess their relationship to methylphenidate-induced changes in brain dopamine. The intensity of the "high" induced by methylphenidate was significantly correlated with the levels of released dopamine (r = 0.78, p <.001); subjects having the greatest increases were those who perceived the most intense high. This relationship remained significant after partialing out for dose and concentration of methylphenidate in plasma. Furthermore, subjects for whom methylphenidate did not increase dopamine did not perceive a high. These results represent the first clear demonstration that stimulant-induced high, a mood descriptor that reflects reinforcing effects of drugs in humans, is associated with increases in brain dopamine, and also that there is a quantitative relationship between levels of D(2) receptor occupancy by dopamine and the intensity of the high.
Assuntos
Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Metilfenidato/farmacologia , Receptores de Dopamina D2/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Cintilografia , Receptores de Dopamina D2/efeitos dos fármacos , Reforço PsicológicoRESUMO
OBJECTIVE: This study assessed whether brain dopamine D2 receptor levels, which show significant intersubject variability, predict reinforcing responses to psychostimulants in humans. METHOD: [11C]Raclopride and positron emission tomography were used to measure D2 receptor levels in 23 healthy men (mean age = 34 years, SD = 7) who had no drug abuse histories in order to assess if there were differences between the subjects who liked and those who disliked the effects of intravenous methylphenidate (0.5 mg/kg). RESULTS: Subjects who liked the effects of methylphenidate had significantly lower D2 receptor levels (mean = 2.72 Bmax/Kd, SD = 0.3) than subjects who disliked its effects (mean = 3.16, SD = 0.3). Moreover, the higher the D2 levels found, the more intense were methylphenidate's unpleasant effects. CONCLUSIONS: These results provide preliminary evidence that D2 receptor levels predict response to psychostimulants in humans and that low D2 receptors may contribute to psychostimulant abuse by favoring pleasant response.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/química , Corpo Estriado/diagnóstico por imagem , Metilfenidato/farmacologia , Receptores de Dopamina D2/análise , Reforço Psicológico , Adulto , Radioisótopos de Carbono , Corpo Estriado/efeitos dos fármacos , Antagonistas de Dopamina , Humanos , Masculino , Racloprida , Receptores de Dopamina D2/efeitos dos fármacos , Recompensa , Salicilamidas , Transtornos Relacionados ao Uso de Substâncias/etiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Tomografia Computadorizada de EmissãoRESUMO
UNLABELLED: The measure of changes in synaptic dopamine (DA) concentration in response to the psychostimulant drug methylphenidate (MP) has been used as an indicator of responsiveness of the DA system. The purpose of this study was to assess the reproducibility of these measures. METHODS: Seven healthy subjects were scanned with PET and [11C]raclopride twice in the same day: 7 min after placebo or methylphenidate (0.5 mg/kg) administration. In parallel we also measured the physiologic and behavioral responses to placebo and to methylphenidate. The same procedures were repeated 1-2 wk later to assess test-retest reproducibility. RESULTS: Measures of plasma to brain transfer constant (K1), striatal distribution volume (DVstr) and DA D2 receptor availability (Bmax/Kd), for the placebo condition were similar for the first (E1) and second (E2) evaluations (Bmax/Kd, E1: 2.77+/-0.44; E2: 2.97+/-0.44). MP administration did not change K1, but it significantly decreased DVstr (E1: -25.9%+/-8.7%, P < or = 0.0002; E2: -20.7%+/-11.7%, P < or = 0.007) and Bmax/Kd (E1: -18.4%+/-8.7%, P < or = 0.002; E2: -13.4%+/-9.2%, P < or = 0.008), and the magnitude of these changes, though lower for E2, did not differ significantly. MP increased pulse rate (E1: +64%+/-43%, P < or = 0.002; E2: +69%+/-33%, P < or = 0.001), systolic pressure (E1: +37%+/-19%, P < or = 0.0006; E2: +29%+/-15%, P < or = 0.0009), self reports for drug effects (0: nothing to 10: extreme) of "rush" (E1: +8+/-3, P < or = 0.0004; E2: +6+/-4, P < or = 0.01) and "high" (E1: +8+/-3, P < or = 0.0001, E2: +8+/-3, P < or = 0.0003), anxiety (E1: +5+/-4, P < or = 0.02; E2: +4+/-4, P = 0.1) and restlessness (E1: +4+/-4, P < or = 0.04; E2: +4+/-5, P = 0.1). The magnitude of the cardiovascular and behavioral effects did not differ between E1 and E2. CONCLUSION: MP-induced changes in striatal DV and in Bmax/Kd, as well as the behavioral and cardiovascular effects, were reproducible with repeated administration.
Assuntos
Encéfalo/diagnóstico por imagem , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Dopamina/metabolismo , Dopamina/metabolismo , Metilfenidato/farmacologia , Salicilamidas/metabolismo , Adulto , Ligação Competitiva , Encéfalo/metabolismo , Radioisótopos de Carbono , Feminino , Humanos , Cinética , Masculino , Racloprida , Reprodutibilidade dos Testes , Tomografia Computadorizada de EmissãoRESUMO
Formation of new blood vessels is a prerequisite for outgrowth of solid tumours and metastasis. Leukaemia and lymphoma are also dependent on angiogenesis. Inhibition of angiogenesis is therefore a promising therapy for all cancer types. Angiogenic factors reduce the expression of tumour endothelial adhesion molecules for leukocytes, which enables tumours to escape the inflammation response. Antiangiogenic factors induce not only starvation of the tumour owing to deprivation of vasculature, but also re-expression of adhesion molecules, resulting in increased leukocyte infiltration. On the basis of de novo design of chemokines with antiangiogenic properties, novel inhibitors of angiogenesis are developed and selected for their ability to induce a tumour inflammatory reaction.
Assuntos
Indutores da Angiogênese/antagonistas & inibidores , Antineoplásicos/farmacologia , Leucócitos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Indutores da Angiogênese/metabolismo , Antineoplásicos/uso terapêutico , Moléculas de Adesão Celular/metabolismo , Humanos , Neovascularização Patológica/metabolismoRESUMO
The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidate's side effects may counterbalance its reinforcing effects.