RESUMEN
Psychopathy is characterized by antisocial behavior, poor behavioral control and lacking empathy, and structural alterations in the corresponding neural circuits. Molecular brain basis of psychopathy remains poorly characterized. Here we studied type 2 dopamine receptor (D2R) and mu-opioid receptor (MOR) availability in convicted violent offenders with high psychopathic traits (n = 11) and healthy matched controls (n = 17) using positron emission tomography (PET). D2R were measured with radioligand [11C]raclopride and MORs with radioligand [11C]carfentanil. Psychopathic subjects had lowered D2R availability in caudate and putamen, and striatal D2R availability was also associated with degree of psychopathic traits in this prisoner sample. No group differences were found in MOR availability, although in the prisoner sample, psychopathic traits were negatively correlated with MOR availability in the amygdala and nucleus accumbens. We conclude that D2R signaling could be the putative neuromolecular pathway for psychopathy, whereas evidence for alterations in the MOR system is more limited.
Asunto(s)
Trastorno de Personalidad Antisocial , Criminales , Tomografía de Emisión de Positrones , Receptores de Dopamina D2 , Violencia , Humanos , Receptores de Dopamina D2/metabolismo , Masculino , Trastorno de Personalidad Antisocial/diagnóstico por imagen , Trastorno de Personalidad Antisocial/metabolismo , Adulto , Tomografía de Emisión de Positrones/métodos , Receptores Opioides mu/metabolismo , Racloprida/farmacocinética , Adulto Joven , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Fentanilo/análogos & derivadosRESUMEN
Whole-brain mapping of drug effects are needed to understand the neural underpinnings of drug-related behaviors. Amphetamine administration is associated with robust increases in striatal dopamine (DA) release. Dopaminergic terminals are, however, present across several associative brain regions, which may contribute to behavioral effects of amphetamine. Yet the assessment of DA release has been restricted to a few brain regions of interest. The present work employed positron emission tomography (PET) with [11C]raclopride to investigate regional and temporal characteristics of amphetamine-induced DA release across twenty sessions in adult female Sprague Dawley rats. Amphetamine was injected intravenously (2 mg/kg) to cause displacement of [11C]raclopride binding from DA D2-like receptors, assessed using temporally sensitive pharmacokinetic PET model (lp-ntPET). We show amphetamine-induced [11C]raclopride displacement in the basal ganglia, and no changes following saline injections. Peak occupancy was highest in nucleus accumbens, followed by caudate-putamen and globus pallidus. Importantly, significant amphetamine-induced displacement was also observed in several extrastriatal regions, and specifically in thalamus, insula, orbitofrontal cortex, and secondary somatosensory area. For these, peak occupancy occurred later and was lower as compared to the striatum. Collectively, these findings demonstrate distinct amphetamine-induced DA responses across the brain, and that [11C]raclopride-PET can be employed to detect such spatiotemporal differences.
Asunto(s)
Anfetamina , Dopamina , Femenino , Ratas , Animales , Anfetamina/farmacología , Anfetamina/metabolismo , Racloprida/farmacocinética , Dopamina/metabolismo , Ratas Sprague-Dawley , Tomografía de Emisión de Positrones/métodos , Encéfalo/metabolismo , Cuerpo Estriado/metabolismoRESUMEN
BACKGROUND: Between unaffected mental health and diagnosable psychiatric disorders, there is a vast continuum of functioning. The hypothesized link between striatal dopamine signaling and psychosis has guided a prolific body of research. However, it has been understudied in the context of multiple interacting factors, subclinical phenotypes, and pre-postsynaptic dynamics. METHOD: This work investigated psychotic-like experiences and D2/3 dopamine postsynaptic receptor availability in the dorsal striatum, quantified by in vivo [11C]-raclopride positron emission tomography, in a sample of 24 healthy male individuals. Additional mediation and moderation effects with childhood trauma and key dopamine-regulating genes were examined. RESULTS: An inverse relationship between nondisplaceable binding potential and subclinical symptoms was identified. D2/3 receptor availability in the left putamen fully mediated the association between traumatic childhood experiences and odd beliefs, that is, inclinations to see meaning in randomness and unfounded interpretations. Moreover, the effect of early adversity was moderated by a DRD2 functional variant (rs1076560). The results link environmental and neurobiological influences in the striatum to the origination of psychosis spectrum symptomology, consistent with the social defeat and diathesis-stress models. CONCLUSIONS: Adversity exposure may affect the dopamine system as in association with biases in probabilistic reasoning, attributional style, and salience processing. The inverse relationship between D2/3 availability and symptomology may be explained by endogenous dopamine occupying the receptor, postsynaptic compensatory mechanisms, and/or altered receptor sensitivity. This may also reflect a cognitively stabilizing mechanism in non-help-seeking individuals. Future research should comprehensively characterize molecular parameters of dopamine neurotransmission along the psychosis spectrum and according to subtype profiling.
Asunto(s)
Experiencias Adversas de la Infancia , Antagonistas de los Receptores de Dopamina D2/farmacocinética , Dopamina/metabolismo , Neostriado/metabolismo , Trauma Psicológico/metabolismo , Trastornos Psicóticos/metabolismo , Receptores de Dopamina D2/metabolismo , Adulto , Adultos Sobrevivientes de Eventos Adversos Infantiles , Femenino , Humanos , Masculino , Neostriado/diagnóstico por imagen , Tomografía de Emisión de Positrones , Trauma Psicológico/diagnóstico por imagen , Trauma Psicológico/fisiopatología , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/fisiopatología , Racloprida/farmacocinética , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/metabolismoRESUMEN
BACKGROUND: Transdermal antipsychotic patch formulations offer potential benefits, including improved adherence. This study investigated the striatal dopamine D2 receptor occupancy with daily blonanserin transdermal patch application. METHODS: This open-label, phase II study enrolled 18 Japanese outpatients (20 to <65 years) with schizophrenia (DSM-IV-TR criteria; total Positive and Negative Syndrome Scale score <120 at screening) treated with blonanserin 8-mg or 16-mg tablets. Patients continued tablets for 2-4 weeks at their current dose and were then assigned to once-daily blonanserin patches (10/20/40/60/80 mg daily) for 2-4 weeks based on the oral dose. [11C]raclopride positron emission tomography scanning determined blonanserin striatal dopamine D2 receptor occupancy (primary endpoint). Secondary endpoints included assessment of receptor occupancy by dose, changes in Positive and Negative Syndrome Scale and Clinical Global Impressions-Severity of Illness-Severity scores, patient attitudes towards adherence, and patch adhesiveness. RESULTS: Of 18 patients who started the blonanserin tablet treatment period, 14 patients completed treatment. Mean D2 receptor occupancy for blonanserin tablets 8 mg/d (59.2%, n = 5) and 16 mg/d (66.3%, n = 9) was within the values for blonanserin patches: 10 mg/d (33.3%, n = 3), 20 mg/d (29.9%, n = 2), 40 mg/d (61.2%, n = 3), 60 mg/d (59.0%, n = 3), and 80 mg/d (69.9%, n = 3). Occupancy generally increased with increasing blonanserin dose for both formulations with the half maximal receptor occupancy for tablets and patches associated with doses of 6.9 mg/d and 31.9 mg/d, respectively. Diurnal variability in occupancy was lower during transdermal patch treatment than during tablet treatment. Blonanserin transdermal patches were well tolerated with no major safety concerns. CONCLUSIONS: Blonanserin patches (40/80 mg/d) have lower diurnal variability in occupancy than blonanserin tablets (8/16 mg/d), and patches at doses of 40 mg/d and 80 mg/d appear to be a suitable alternative for blonanserin tablets at doses of 8 mg/d and 16 mg/d, respectively. Blonanserin patches represent a potential new treatment option for patients with schizophrenia. TRIAL REGISTRY: JAPIC Clinical Trials Information registry (www.clinicaltrials.jp; JapicCTI-No: JapicCTI-121914).
Asunto(s)
Antipsicóticos/farmacocinética , Cuerpo Estriado/efectos de los fármacos , Piperazinas/farmacocinética , Piperidinas/farmacocinética , Receptores de Dopamina D2/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Adulto , Antipsicóticos/administración & dosificación , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperidinas/administración & dosificación , Tomografía de Emisión de Positrones , Racloprida/farmacocinética , Parche Transdérmico , Adulto JovenRESUMEN
Measurement of stimulus-induced dopamine release and other types of transient neurotransmitter response (TNR) from dynamic positron emission tomography (PET) images typically suffers from limited detection sensitivity and high false positive (FP) rates. Measurement of TNR of a voxel-level can be particularly problematic due to high image noise. In this work, we perform voxel-level TNR detection using artificial neural networks (ANN) and compare their performance to previously used standard statistical tests. Different ANN architectures were trained and tested using simulated and real human PET imaging data, obtained with the tracer [11C]raclopride (a D2 receptor antagonist). A distinguishing feature of our approach is the use of 'personalized' ANNs that are designed to operate on the image from a specific subject and scan. Training of personalized ANNs was performed using simulated images that have been matched with the acquired image in terms of the signal, resolution, and noise. In our tests of TNR detection performance, the F-test of the linear parametric neurotransmitter PET model fit residuals was used as the reference method. For a moderate TNR magnitude, the areas under the receiver operating characteristic curves in simulated tests were 0.64 for the F-test and 0.77-0.79 for the best ANNs. At a fixed FP rate of 0.01, the true positive rates were 0.6 for the F-test and 0.8-0.9 for the ANNs. The F-test detected on average 28% of a 8.4 mm cluster with a strong TNR, while the best ANN detected 47%. When applied to a real image, no significant abnormalities in the ANN outputs were observed. These results demonstrate that personalized ANNs may offer a greater detection sensitivity of dopamine release and other types of TNR compared to previously used method based on the F-test.
Asunto(s)
Encéfalo/metabolismo , Radioisótopos de Carbono/análisis , Redes Neurales de la Computación , Neurotransmisores/metabolismo , Tomografía de Emisión de Positrones/métodos , Medicina de Precisión , Racloprida/farmacocinética , Encéfalo/diagnóstico por imagen , Antagonistas de Dopamina/farmacocinética , Humanos , Tasa de Depuración Metabólica , Neurotransmisores/análisis , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
Pharmacological magnetic resonance imaging (phMRI) allows the visualization of brain pharmacological effects of drugs using functional MRI (fMRI). phMRI can help us facilitate central nervous system (CNS) drug development. However, there have been few studies demonstrating the dose relationship of the fMRI response induced by CNS drugs to underlying target engagement or behavioral efficacy. To clarify these relationships, we examined receptor occupancy measurements using positron emission tomography (PET) (n = 3~5), fMRI (n = 5~8) and a cataleptic behavior (n = 6) with raclopride, a dopamine D2 receptor antagonist (8, 20, and 200 µg/kg) on Wistar rats. Dopamine D2 receptor occupancy was increased dose dependently by raclopride (41.8 ± 2.7%, 8 µg/kg; 64.9 ± 2.8%, 20 µg/kg; 83.1 ± 3.0%, 200 µg/kg). phMRI study revealed significant positive responses to raclopride at 200 µg/kg specifically in the striatum and nucleus accumbens, related to dopaminergic system. Slight fMRI responses were observed at 20 µg/kg in some areas corresponding to the striatum and nucleus accumbens. There were no noticeable fMRI responses at 8 µg/kg raclopride administration. Raclopride at 200 µg/kg significantly increased the cataleptic score, although, at 8 and 20 µg/kg, raclopride had no significant effects. These findings showed that raclopride-induced fMRI responses were observed at doses inducing cataleptic behavior and high D2 receptor occupancy, suggesting that phMRI can be useful for dose selection in clinical trial as an evaluation method of brain activity, which reflects behavioral responses induced by target engagements.
Asunto(s)
Cuerpo Estriado/metabolismo , Antagonistas de Dopamina/farmacocinética , Reacción Cataléptica de Congelación/efectos de los fármacos , Núcleo Accumbens/metabolismo , Racloprida/farmacocinética , Animales , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/fisiología , Imagen por Resonancia Magnética , Masculino , Núcleo Accumbens/diagnóstico por imagen , Núcleo Accumbens/fisiología , Tomografía de Emisión de Positrones , Unión Proteica , Ratas , Ratas Wistar , Receptores de Dopamina D2/metabolismoRESUMEN
Application of kinetic modeling (KM) on a voxel level in dynamic PET images frequently suffers from high levels of noise, drastically reducing the precision of parametric image analysis. In this paper, we investigate the use of machine learning and artificial neural networks to denoise dynamic PET images. We train a deep denoising autoencoder (DAE) using noisy and noise-free spatiotemporal image patches, extracted from the simulated images of [11C]raclopride, a dopamine D2 receptor agonist. The DAE-processed dynamic and corresponding parametric images (simulated and acquired) are compared with those obtained with conventional denoising techniques, including temporal and spatial Gaussian smoothing, iterative spatiotemporal smoothing/deconvolution, and the highly constrained backprojection processing (HYPR). The simulated (acquired) parametric image non-uniformity was 7.75% (19.49%) with temporal and 5.90% (14.50%) with spatial smoothing, 5.82% (16.21%) with smoothing/deconvolution, 5.49% (13.38%) with HYPR, and 3.52% (11.41%) with DAE. The DAE also produced the best results in terms of the coefficient of variation of voxel values and structural similarity index. Denoising-induced bias in the regional mean binding potential was 7.8% with temporal and 26.31% with spatial smoothing, 28.61% with smoothing/deconvolution, 27.63% with HYPR, and 14.8% with DAE. When the test data did not match the training data, erroneous outcomes were obtained. Our results demonstrate that a deep DAE can provide a substantial reduction in the voxel-level noise compared with the conventional spatiotemporal denoising methods while introducing a similar or lower amount of bias. The better DAE performance comes at the cost of lower generality and requiring appropriate training data.
Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Redes Neurales de la Computación , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Humanos , Aprendizaje Automático , Fantasmas de Imagen , Racloprida/farmacocinéticaRESUMEN
In vivo dopamine D2-receptor availability is frequently assessed with 11C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for 11C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal 11C-raclopride binding potential (BPND) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test-retest reliability in a sample of younger adults. The present work demonstrates high seven-month test-retest reliability of striatal and extrastriatal 11C-raclopride BPND values in healthy, older adults (n = 27, age: 64-78 years). Mean 11C-raclopride BPND values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85-0.96), absolute variability was low (mean: 4-8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional 11C-raclopride BPND values correlated with previously determined 18F-fallypride BPND values (ρ = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: ρ = 0.92; p < 0.001; excluding striatum: ρ = 0.75; p = 0.067). These observations suggest that extrastriatal 11C-raclopride measurements represent a true D2 signal.
Asunto(s)
Cuerpo Estriado/diagnóstico por imagen , Agonistas de Dopamina/farmacocinética , Tomografía de Emisión de Positrones/métodos , Racloprida/farmacocinética , Receptores de Dopamina D2/metabolismo , Adulto , Anciano , Benzamidas , Radioisótopos de Carbono , Corteza Cerebral/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pirrolidinas , Radiofármacos , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
[11C]raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D2/3R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [11C]raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [11C]raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [11C]raclopride: (i) To assess the validity of extrastriatal [11C]raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D2/3R antagonist. (ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BPND) was quantified using the simplified reference tissue model with cerebellum as reference. Quetiapine dosing was associated with decrease in [11C]raclopride BPND in temporal cortex (18⯱â¯17% occupancy) and thalamus (20⯱â¯17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51⯱â¯4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [11C]raclopride PET, quantified using cerebellum as reference, is not a suitable tool to measure D2/3R in extrastriatal regions.
Asunto(s)
Encéfalo/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Racloprida/farmacocinética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Adulto , Antagonistas de los Receptores de Dopamina D2/farmacocinética , Humanos , Masculino , Fumarato de Quetiapina/farmacocinética , Ensayo de Unión Radioligante , Receptores de Dopamina D3/antagonistas & inhibidores , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Transcranial direct-current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) has been established as an effective and noninvasive method to modulate cognitive function. Nevertheless, the mechanisms causing those cognitive changes under the tDCS remain largely unknown. We strove to elucidate the cognito-biological relation under the tDCS condition by examining whether the dopamine system activated by tDCS is involved in cognitive changes in human participants, or not. To evaluate the dopamine system, we used [11C]-raclopride positron emission tomography (PET) scanning: 20 healthy men underwent two [11C]-raclopride PET scans and subsequent neuropsychological tests. One scan was conducted after tDCS to the DLPFC. One was conducted after sham stimulation (control). Results of [11C]-raclopride PET measurements demonstrate that tDCS to the DLPFC caused dopamine release in the right ventral striatum. Neuropsychological tests for attentiveness revealed that tDCS to the DLPFC-enhanced participants' accuracy. Moreover, this effect was correlated significantly with dopamine release. This finding provides clinico-biological evidence, demonstrating that enhancement of dopamine signaling by tDCS in the ventral striatum is associated with attention enhancement.
Asunto(s)
Atención , Dopamina/fisiología , Corteza Prefrontal/fisiología , Estimulación Transcraneal de Corriente Directa , Estriado Ventral/fisiología , Adulto , Estudios Cruzados , Antagonistas de Dopamina/farmacocinética , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/efectos de los fármacos , Racloprida/farmacocinética , Estriado Ventral/diagnóstico por imagen , Adulto JovenRESUMEN
Computational methods, such as the linear parametric neurotransmitter PET (lp-ntPET) method, have been developed to characterize the transient changes in radiotracer kinetics in the target tissue during endogenous neurotransmitter release. In this paper, we describe and evaluate a parametric reconstruction algorithm that uses an expectation maximization framework, along with the lp-ntPET model, to estimate the endogenous neurotransmitter response to stimuli directly from the measured PET data. Computer simulations showed that the proposed direct reconstruction method offers improved accuracy and precision for the estimated timing parameters of the neurotransmitter response at the voxel level ( td=1±2 min, for activation onset bias and standard deviation) compared with conventional post reconstruction modeling ( td=4±7 min). In addition, we applied the proposed direct parameter estimation methodology to a [11C]raclopride displacement study of an awake rat and generated parametric maps illustrating the magnitude of ligand displacement from striatum. Although the estimated parametric maps of activation magnitude obtained from both direct and post reconstruction methodologies suffered from false positive activations, the proposed direct reconstruction framework offered more reliable parametric maps when the activation onset parameter was constrained.
Asunto(s)
Encéfalo/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Neurotransmisores/metabolismo , Tomografía de Emisión de Positrones/métodos , Algoritmos , Animales , Encéfalo/metabolismo , Encéfalo/fisiología , Simulación por Computador , Masculino , Fantasmas de Imagen , Racloprida/farmacocinética , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
The potential effects of changes in blood flow on the delivery and washout of radiotracers has been an ongoing question in PET bolus injection studies. This study provides practical insight into this topic by experimentally measuring cerebral blood flow (CBF) and neuroreceptor binding using simultaneous PET/MRI. Hypercapnic challenges (7% CO2) were administered to non-human primates in order to induce controlled increases in CBF, measured with pseudo-continuous arterial spin labeling. Simultaneously, dopamine D2/D3 receptor binding of [11C]raclopride or [18F]fallypride was monitored with dynamic PET. Experiments showed that neither time activity curves nor quantification of binding through binding potentials ( BPND) were measurably affected by CBF increases, which were larger than two-fold. Simulations of experimental procedures showed that even large changes in CBF should have little effect on the time activity curves of radiotracers, given a set of realistic assumptions. The proposed method can be applied to experimentally assess the flow sensitivity of other radiotracers. Results demonstrate that CBF changes, which often occur due to behavioral tasks or pharmacological challenges, do not affect PET [11C]raclopride or [18F]fallypride binding studies and their quantification. The results from this study suggest flow effects may have limited impact on many PET neuroreceptor tracers with similar properties.
Asunto(s)
Circulación Cerebrovascular/fisiología , Papio/fisiología , Radiofármacos/farmacocinética , Células Receptoras Sensoriales/metabolismo , Animales , Conducta Animal/fisiología , Benzamidas/farmacocinética , Simulación por Computador , Femenino , Imagen por Resonancia Magnética , Masculino , Imagen Multimodal , Tomografía de Emisión de Positrones , Desempeño Psicomotor/fisiología , Racloprida/farmacocinética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Marcadores de SpinRESUMEN
Dopamine D2 receptor occupancy (D2RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D2RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the present study was to determine D2RO at plasma steady state of 60 mg ITI-007, a dose that previously demonstrated antipsychotic efficacy in a controlled trial, administered orally open-label once daily in the morning for two weeks in patients with schizophrenia (N = 10) and after at least a two-week washout period from standard of care antipsychotics. D2RO was determined using positron emission tomography with 11C-raclopride as the radiotracer. Mean peak dorsal striatal D2RO was 39% at 60 mg ITI-007 occurring 1 h post-dose. Lumateperone was well-tolerated with a favorable safety profile in this study. There were no clinically significant changes in vital signs, ECGs, or clinical chemistry laboratory values, including prolactin levels. There were no adverse event reports of akathisia or other extrapyramidal motor side effects; mean scores on motor function scales indicated no motor disturbances with lumateperone treatment. This level of occupancy is lower than most other antipsychotic drugs at their efficacious doses and likely contributes to the favorable safety and tolerability profile of lumateperone with reduced risk for movement disorders and hyperprolactinemia. If approved, lumateperone may provide a new and safe treatment option for individuals living with schizophrenia.
Asunto(s)
Antipsicóticos/farmacocinética , Butirofenonas/farmacocinética , Neostriado/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Adulto , Radioisótopos de Carbono , Antagonistas de los Receptores de Dopamina D2/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neostriado/diagnóstico por imagen , Tomografía de Emisión de Positrones , Racloprida/farmacocinética , Esquizofrenia/diagnóstico por imagenRESUMEN
Between-person differences in cognitive performance in older age are associated with variations in physical activity. The neurotransmitter dopamine (DA) contributes to cognitive performance, and the DA system deteriorates with advancing age. Animal data and a patient study suggest that physical activity modulates DA receptor availability, but data from healthy humans are lacking. In a cross-sectional study with 178 adults aged 64-68 years, we investigated links among self-reported physical activity, D2/D3 DA receptor (D2/3DR) availability, and cognitive performance. D2/3DR availability was measured with [11C]raclopride positron emission tomography at rest. We used structural equation modeling to obtain latent factors for processing speed, episodic memory, working memory, physical activity, and D2/3DR availability in caudate, putamen, and hippocampus. Physical activity intensity was positively associated with D2/3DR availability in caudate, but not putamen and hippocampus. Frequency of physical activity was not related to D2/3DR availability. Physical activity intensity was positively related to episodic memory and working memory. D2/3DR availability in caudate and hippocampus was positively related to episodic memory. Taken together, our results suggest that striatal DA availability might be a neurochemical correlate of episodic memory that is also associated with physical activity.
Asunto(s)
Envejecimiento/fisiología , Núcleo Caudado/metabolismo , Antagonistas de Dopamina/farmacocinética , Ejercicio Físico/fisiología , Hipocampo/metabolismo , Memoria Episódica , Memoria a Corto Plazo/fisiología , Tomografía de Emisión de Positrones/métodos , Receptores de Dopamina D2/metabolismo , Anciano , Envejecimiento/metabolismo , Núcleo Caudado/diagnóstico por imagen , Femenino , Hipocampo/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Putamen/diagnóstico por imagen , Putamen/metabolismo , Racloprida/farmacocinética , Receptores de Dopamina D3/metabolismoRESUMEN
Individuals differ in how they perceive, remember, and think. There is evidence for the existence of distinct subgroups that differ in cognitive performance within the older population. However, it is less clear how individual differences in cognition in old age are linked to differences in brain-based measures. We used latent-profile analysis on n-back working-memory (WM) performance to identify subgroups in a large sample of older adults (n = 181; age = 64-68 years). Our analysis identified one larger normal subgroup with higher performance (n = 113; 63%), and a second smaller subgroup (n = 55; 31%) with lower performance. The low-performing subgroup showed weaker load-dependent BOLD modulation and lower connectivity within the fronto-parietal network (FPN) as well as between FPN and striatum during n-back, along with lower FPN connectivity at rest. This group also exhibited lower FPN structural integrity, lower frontal dopamine D2 binding potential, inferior performance on offline WM tests, and a trend-level genetic predisposition for lower dopamine-system efficiency. By contrast, this group exhibited relatively intact episodic memory and associated brain measures (i.e., hippocampal volume, structural, and functional connectivity within the default-mode network). Collectively, these data provide converging evidence for the existence of a group of older adults with impaired WM functioning characterized by reduced cortico-striatal coupling and aberrant cortico-cortical integrity within FPN.
Asunto(s)
Envejecimiento/fisiología , Encéfalo/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Trastornos de la Memoria/complicaciones , Memoria a Corto Plazo/fisiología , Anciano , Presión Sanguínea/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fosfoproteína 32 Regulada por Dopamina y AMPc/genética , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Masculino , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/genética , Recuerdo Mental , Persona de Mediana Edad , Mutación/genética , Pruebas Neuropsicológicas , Oxígeno/sangre , Racloprida/farmacocinética , Receptores de Dopamina D2/genética , Percepción del Tiempo/fisiología , Aprendizaje Verbal/fisiologíaRESUMEN
A single transcranial direct current stimulation (tDCS) session applied over the dorsolateral prefrontal cortex (DLFPC) can be associated with procognitive effects. Furthermore, repeated DLPFC tDCS sessions are under investigation as a new therapeutic tool for a range of neuropsychiatric conditions. A possible mechanism explaining such beneficial effects is a modulation of meso-cortico-limbic dopamine transmission. We explored the spatial and temporal neurobiological effects of bifrontal tDCS on subcortical dopamine transmission during and immediately after the stimulation. In a double blind sham-controlled study, 32 healthy subjects randomly received a single session of either active (20 min, 2 mA; n = 14) or sham (n = 18) tDCS during a dynamic positron emission tomography scan using [11C]raclopride binding. During the stimulation period, no significant effect of tDCS was observed. After the stimulation period, compared with sham tDCS, active tDCS induced a significant decrease in [11C]raclopride binding potential ratio in the striatum, suggesting an increase in extracellular dopamine in a part of the striatum involved in the reward-motivation network. The present study provides the first evidence that bifrontal tDCS induces neurotransmitter release in polysynaptic connected subcortical areas. Therefore, levels of dopamine activity and reactivity should be a new element to consider for a general hypothesis of brain modulation by bifrontal tDCS.
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Dopamina/metabolismo , Corteza Prefrontal/fisiología , Estimulación Transcraneal de Corriente Directa/métodos , Estriado Ventral/metabolismo , Adulto , Análisis de Varianza , Antagonistas de Dopamina/farmacocinética , Método Doble Ciego , Femenino , Lateralidad Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/efectos de los fármacos , Racloprida/farmacocinética , Factores de Tiempo , Estriado Ventral/diagnóstico por imagen , Estriado Ventral/fisiología , Adulto JovenRESUMEN
PURPOSE: Positron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BPND) of [11C]raclopride in NHP. PROCEDURES: Three cynomolgus monkeys underwent two to three PET measurements with [11C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BPND in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region. RESULTS: In each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman's ρ = - 0.79, p = 0.03), but not with BPND (ρ = - 0.25, p = 0.55). CONCLUSIONS: These data suggest that sevoflurane affects the shape of TACs but has no evident effect on BPND in consecutive PET measurements.
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Anestesia , Radioisótopos de Carbono/farmacocinética , Racloprida/farmacocinética , Sevoflurano/farmacología , Animales , Cerebelo/metabolismo , Cuerpo Estriado/metabolismo , Femenino , Cinética , Primates , Factores de TiempoRESUMEN
Intranasal drug delivery is a noninvasive drug delivery route that can enhance systemic delivery of therapeutics with poor oral bioavailability by exploiting the rich microvasculature within the nasal cavity. The intranasal delivery route has also been targeted as a method for improved brain uptake of neurotherapeutics, with a goal of harnessing putative, direct nose-to-brain pathways. Studies in rodents, nonhuman primates, and humans have pointed to the efficacy of intranasally delivered neurotherapeutics, while radiolabeling studies have analyzed brain uptake following intranasal administration. In the present study, we employed carbon-11 radioactive methylation to assess the pharmacokinetic mechanism of intranasal delivery of Orexin A, a native neuropeptide and prospective antinarcoleptic drug that binds the orexin receptor 1. Using physicochemical and pharmacological analysis, we identified the methylation sites and confirmed the structure and function of methylated Orexin A (CH3-Orexin A) prior to monitoring its brain uptake following intranasal administration in rodent and nonhuman primate. Through positron emission tomography (PET) imaging of [11C]CH3-Orexin A, we determined that the brain exposure to Orexin A is poor after intranasal administration. Additional ex vivo analysis of brain uptake using [125I]Orexin A indicated intranasal administration of Orexin A affords similar brain uptake when compared to intravenous administration across most brain regions, with possible increased brain uptake localized to the olfactory bulbs.
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Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono , Orexinas/administración & dosificación , Tomografía de Emisión de Positrones , Promotores de la Vigilia/administración & dosificación , Administración Intranasal , Animales , Encéfalo/metabolismo , Macaca mulatta , Masculino , Metilación , Estructura Molecular , Orexinas/síntesis química , Orexinas/química , Orexinas/farmacocinética , Tomografía de Emisión de Positrones/métodos , Racloprida/administración & dosificación , Racloprida/farmacocinética , Ratas Sprague-Dawley , Promotores de la Vigilia/síntesis química , Promotores de la Vigilia/química , Promotores de la Vigilia/farmacocinéticaRESUMEN
BACKGROUND: Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC-MS based approach. METHODS: Rats (n=24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61µmol/kg, i.e. 0.56mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n=7) to measure the free drug concentration in the extracellular fluid of the striatum and cerebellum. Raclopride concentrations in all samples were analyzed by LC-MS. A population PK-RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics. RESULTS: In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10-h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO <10%), sub-pharmacological dose (RO 10%-30%) and pharmacological dose (RO >30%). CONCLUSION: For the first time a predictive model that could describe the quantitative in vivo relationship between dose, PK and D2 RO of raclopride in non-anesthetized rat was established. The PK-RO model could facilitate the selection of optimal dose and dosing time when raclopride is used as tracer or as pharmacological blocker in various rat studies. The LC-MS based approach, which doses and quantifies a non-radiolabeled tracer, could be useful in evaluating the systemic disposition and brain kinetics of tracers.
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Antipsicóticos/farmacocinética , Antagonistas de los Receptores de Dopamina D2/farmacocinética , Racloprida/farmacocinética , Receptores de Dopamina D2/metabolismo , Animales , Antipsicóticos/farmacología , Encéfalo/metabolismo , Dopamina/metabolismo , Antagonistas de los Receptores de Dopamina D2/farmacología , Masculino , Racloprida/farmacología , RatasRESUMEN
Background: Dopamine D2 receptors are reported to have high-affinity (D2High) and low-affinity (D2Low) states. Although an increased proportion of D2High has been demonstrated in animal models of schizophrenia, few clinical studies have investigated this alteration of D2High in schizophrenia in vivo. Methods: Eleven patients with schizophrenia, including 10 antipsychotic-naive and 1 antipsychotic-free individuals, and 17 healthy controls were investigated. Psychopathology was assessed by Positive and Negative Syndrome Scale, and a 5-factor model was used. Two radioligands, [11C]raclopride and [11C]MNPA, were employed to quantify total dopamine D2 receptor and D2High, respectively, in the striatum by measuring their binding potentials. Binding potential values of [11C]raclopride and [11C]MNPA and the binding potential ratio of [11C]MNPA to [11C]raclopride in the striatal subregions were statistically compared between the 2 diagnostic groups using multivariate analysis of covariance controlling for age, gender, and smoking. Correlations between binding potential and Positive and Negative Syndrome Scale scores were also examined. Results: Multivariate analysis of covariance demonstrated a significant effect of diagnosis (schizophrenia and control) on the binding potential ratio (P=.018), although the effects of diagnosis on binding potential values obtained with either [11C]raclopride or [11C]MNPA were nonsignificant. Posthoc test showed that the binding potential ratio was significantly higher in the putamen of patients (P=.017). The Positive and Negative Syndrome Scale "depressed" factor in patients was positively correlated with binding potential values of both ligands in the caudate. Conclusions: The present study indicates the possibilities of: (1) a higher proportion of D2High in the putamen despite unaltered amounts of total dopamine D2 receptors; and (2) associations between depressive symptoms and amounts of caudate dopamine D2 receptors in patients with schizophrenia.