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1.
J Pharmacol Toxicol Methods ; 127: 107518, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38797366

RESUMO

Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an indicator of the efficacy and central side effects of antipsychotics because many of these drugs have binding affinities for various receptors, such as dopamine 2 (D2), histamine 1 (H1), and muscarinic acetylcholine (mACh) receptors. The purpose of this study was to develop a method for the simultaneous measurement of multiple receptor occupancies in the brain by the simultaneous quantification of unlabeled tracer levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rats were pre-administered with a vehicle, displacer, or olanzapine, and mixed solutions of raclopride, doxepin, and 3-quinuclidinyl benzilate (3-QNB) were administered (3, 10, and 30 µg/kg). The brain tissue and plasma tracer concentrations were quantified 45 min later using LC-MS/MS, and the binding potential was calculated. The highest binding potential was observed at 3 µg/kg raclopride, 10 µg/kg doxepin, and 30 µg/kg 3-QNB. Tracer-specific binding at these optimal tracer doses in the cerebral cortex was markedly reduced by pre-administration of displacers. D2, H1, and mACh receptor occupancy by olanzapine increased in a dose-dependent manner, reaching 70-95%, 19-43%, and 12-45%, respectively, at an olanzapine dose range of 3-10 mg/kg. These results suggest that simultaneous determination of in vivo D2, H1, and mACh receptor occupancy is possible using LC-MS/MS.


Assuntos
Antipsicóticos , Olanzapina , Ratos Sprague-Dawley , Receptores de Dopamina D2 , Receptores Histamínicos H1 , Receptores Muscarínicos , Espectrometria de Massas em Tandem , Animais , Espectrometria de Massas em Tandem/métodos , Ratos , Masculino , Antipsicóticos/administração & dosagem , Cromatografia Líquida/métodos , Receptores de Dopamina D2/metabolismo , Receptores Muscarínicos/metabolismo , Receptores Muscarínicos/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Olanzapina/farmacocinética , Olanzapina/administração & dosagem , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Benzodiazepinas/análise , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacocinética , Racloprida/metabolismo , Doxepina/farmacocinética , Quinuclidinil Benzilato/metabolismo , Relação Dose-Resposta a Droga
2.
J Affect Disord ; 356: 672-680, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38657771

RESUMO

BACKGROUND: Depression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD. METHODS: Six patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [11C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [11C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BPND) with the cerebellum as reference tissue. RESULTS: Depression and anxiety symptoms improved after 3-6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [11C]raclopride BPND in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01). LIMITATIONS: This study was limited to the small sample size and lack of a healthy control group. CONCLUSIONS: Chronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.


Assuntos
Estimulação Encefálica Profunda , Transtorno Depressivo Resistente a Tratamento , Núcleo Accumbens , Tomografia por Emissão de Pósitrons , Racloprida , Receptores de Dopamina D2 , Humanos , Receptores de Dopamina D2/metabolismo , Estimulação Encefálica Profunda/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Transtorno Depressivo Resistente a Tratamento/terapia , Transtorno Depressivo Resistente a Tratamento/metabolismo , Transtorno Depressivo Resistente a Tratamento/diagnóstico por imagem , Núcleo Accumbens/metabolismo , Núcleo Accumbens/diagnóstico por imagem , Adulto , Núcleos Septais/metabolismo , Núcleos Septais/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Resultado do Tratamento
3.
Neurobiol Aging ; 136: 125-132, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38359585

RESUMO

Dopamine decline is suggested to underlie aging-related cognitive decline, but longitudinal examinations of this link are currently missing. We analyzed 5-year longitudinal data for a sample of healthy, older adults (baseline: n = 181, age: 64-68 years; 5-year follow-up: n = 129) who underwent positron emission tomography with 11C-raclopride to assess dopamine D2-like receptor (DRD2) availability, magnetic resonance imaging to evaluate structural brain measures, and cognitive tests. Health, lifestyle, and genetic data were also collected. A data-driven approach (k-means cluster analysis) identified groups that differed maximally in DRD2 decline rates in age-sensitive brain regions. One group (n = 47) had DRD2 decline exclusively in the caudate and no cognitive decline. A second group (n = 72) had more wide-ranged DRD2 decline in putamen and nucleus accumbens and also in extrastriatal regions. The latter group showed significant 5-year working memory decline that correlated with putamen DRD2 decline, along with higher dementia and cardiovascular risk and a faster biological pace of aging. Taken together, for individuals with more extensive DRD2 decline, dopamine decline is associated with memory decline in aging.


Assuntos
Envelhecimento , Dopamina , Humanos , Idoso , Encéfalo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Racloprida , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/etiologia
4.
Neuropharmacology ; 247: 109862, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38325770

RESUMO

Adenosine A2A-receptors (A2AR) and dopamine D2-receptors (D2R) are known to work together in a synergistic manner. Inhibiting A2ARs by genetic or pharmacological means can relief symptoms and have neuroprotective effects in certain conditions. We applied PET imaging to evaluate the impact of the A2AR antagonist KW6002 on D2R availability and neuroinflammation in an animal model of Parkinson's disease. Male Wistar rats with 6-hydroxydopamine-induced damage to the right striatum were given 3 mg/kg of KW6002 daily for 20 days. Motor function was assessed using the rotarod and cylinder tests, and neuroinflammation and dopamine receptor availability were measured using PET scans with the tracers [11C]PBR28 and [11C]raclopride, respectively. On day 7 and 22 following 6-OHDA injection, rats were sacrificed for postmortem analysis. PET scans revealed a peak in neuroinflammation on day 7. Chronic treatment with KW6002 significantly reduced [11C]PBR28 uptake in the ipsilateral striatum [normalized to contralateral striatum] and [11C]raclopride binding in both striata when compared to the vehicle group. These imaging findings were accompanied by an improvement in motor function. Postmortem analysis showed an 84% decrease in the number of Iba-1+ cells in the ipsilateral striatum [normalized to contralateral striatum] of KW6002-treated rats compared to vehicle rats on day 22 (p = 0.007), corroborating the PET findings. Analysis of tyrosine hydroxylase levels showed less dopaminergic neuron loss in the ipsilateral striatum of KW6002-treated rats compared to controls on day 7. These findings suggest that KW6002 reduces inflammation and dopaminergic neuron loss, leading to less motor symptoms in this animal model of Parkinson's disease.


Assuntos
Doença de Parkinson , Purinas , Ratos , Masculino , Animais , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Dopamina , Receptor A2A de Adenosina/metabolismo , Doenças Neuroinflamatórias , Adenosina/metabolismo , Racloprida , Ratos Wistar , Oxidopamina/toxicidade
5.
Neuropsychopharmacology ; 49(6): 924-932, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38326458

RESUMO

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [11C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, pspin < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (pFDR < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [11C]SCH23390 binding; rho = 0.22, pspin < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r(19) = -0.68, pbonferroni = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.


Assuntos
Encéfalo , Dopamina , Imageamento por Ressonância Magnética , Metilfenidato , Tomografia por Emissão de Pósitrons , Racloprida , Humanos , Masculino , Adulto , Feminino , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Dopamina/metabolismo , Metilfenidato/farmacologia , Metilfenidato/administração & dosagem , Método Duplo-Cego , Adulto Jovem , Racloprida/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Receptores de Dopamina D1/metabolismo , Vias Neurais/efeitos dos fármacos , Vias Neurais/diagnóstico por imagem , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/administração & dosagem , Mapeamento Encefálico
6.
Int J Neuropsychopharmacol ; 27(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38174899

RESUMO

BACKGROUND: Rats emit 50-kHz ultrasonic vocalizations (USVs) in response to nonpharmacological and pharmacological stimuli, with addictive psychostimulants being the most effective drugs that elicit calling behavior in rats. Earlier investigations found that dopamine D1-like and D2-like receptors modulate the emission of 50-kHz USVs stimulated in rats by the acute administration of addictive psychostimulants. Conversely, information is lacking on how dopamine D1-like and D2-like receptors modulate calling behavior in rats that are repeatedly treated with addictive psychostimulants. METHODS: We evaluated the emission of 50-kHz USVs in rats repeatedly treated (×5 on alternate days) with amphetamine (1 mg/kg, i.p.) either alone or together with (1) SCH 23390 (0.1-1 mg/kg, s.c.), a dopamine D1 receptor antagonist; (2) raclopride (0.3-1 mg/kg, s.c.), a selective dopamine D2 receptor antagonist; or (3) a combination of SCH 23390 and raclopride (0.1 + 0.3 mg/kg, s.c.). Calling behavior of rats was recorded following pharmacological treatment, as well as in response to the presentation of amphetamine-paired cues and to amphetamine challenge (both performed 7 days after treatment discontinuation). RESULTS: Amphetamine-treated rats displayed a sensitized 50-kHz USV emission during repeated treatment, as well as marked calling behavior in response to amphetamine-paired cues and to amphetamine challenge. Antagonism of D1 or D2 receptors either significantly suppressed or attenuated the emission of 50-kHz USVs in amphetamine-treated rats, with a maximal effect after synergistic antagonism of both receptors. CONCLUSIONS: These results shed further light on how dopamine transmission modulates the emission of 50-kHz USVs in rats treated with psychoactive drugs.


Assuntos
Anfetamina , Estimulantes do Sistema Nervoso Central , Ratos , Animais , Anfetamina/farmacologia , Dopamina , Antagonistas de Dopamina/farmacologia , Racloprida , Ultrassom , Vocalização Animal , Estimulantes do Sistema Nervoso Central/farmacologia
7.
Phys Med Biol ; 69(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38271737

RESUMO

Objective. Most methods for partial volume correction (PVC) of positron emission tomography (PET) data employ anatomical segmentation of images into regions of interest. This approach is not optimal for exploratory functional imaging beyond regional hypotheses. Here, we describe a novel method for unbiased voxel-wise PVC.Approach.B-spline basis functions were combined with geometric transfer matrices to enable a method (bsGTM) that provides PVC or alternatively provides smoothing with minimal regional crosstalk. The efficacy of the proposed method was evaluated using Monte Carlo simulations, human PET data, and murine functional PET data.Main results.In simulations, bsGTM provided recovery of partial volume signal loss comparable to iterative deconvolution, while demonstrating superior resilience to noise. In a real murine PET dataset, bsGTM yielded much higher sensitivity for detecting amphetamine-induced reduction of [11C]raclopride binding potential. In human PET data, bsGTM smoothing enabled increased signal-to-noise ratios with less degradation of binding potentials relative to Gaussian convolution or non-local means.Significance.bsGTM offers improved performance for PVC relative to iterative deconvolution, the current method of choice for voxel-wise PVC, especially in the common PET regime of low signal-to-noise ratio. The new method provides an anatomically unbiased way to compensate partial volume errors in cases where anatomical segmentation is unavailable or of questionable relevance or accuracy.


Assuntos
Algoritmos , Encéfalo , Humanos , Camundongos , Animais , Tomografia por Emissão de Pósitrons/métodos , Razão Sinal-Ruído , Racloprida , Processamento de Imagem Assistida por Computador/métodos
8.
J Physiol ; 602(3): 461-484, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38165254

RESUMO

Acute cardiovascular physical exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Here, using positron emission tomography (PET) with [11 C]raclopride, in a multi-experiment study we investigated whether acute exercise releases endogenous dopamine (DA) in the brain. We hypothesized that acute exercise augments the brain DA system, and that RT improvement is correlated with this endogenous DA release. The PET study (Experiment 1: n = 16) demonstrated that acute physical exercise released endogenous DA, and that endogenous DA release was correlated with improvements in RT of the Go/No-Go task. Thereafter, using two electrical muscle stimulation (EMS) studies (Experiments 2 and 3: n = 18 and 22 respectively), we investigated what triggers RT improvement. The EMS studies indicated that EMS with moderate arm cranking improved RT, but RT was not improved following EMS alone or EMS combined with no load arm cranking. The novel mechanistic findings from these experiments are: (1) endogenous DA appears to be an important neuromodulator for RT improvement and (2) RT is only altered when exercise is associated with central signals from higher brain centres. Our findings explain how humans rapidly alter their behaviour using neuromodulatory systems and have significant implications for promotion of cognitive health. KEY POINTS: Acute cardiovascular exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Using the neurochemical specificity of [11 C]raclopride positron emission tomography, we demonstrated that acute supine cycling released endogenous dopamine (DA), and that this release was correlated with improved RT. Additional electrical muscle stimulation studies demonstrated that peripherally driven muscle contractions (i.e. exercise) were insufficient to improve RT. The current study suggests that endogenous DA is an important neuromodulator for RT improvement, and that RT is only altered when exercise is associated with central signals from higher brain centres.


Assuntos
Dopamina , Tomografia por Emissão de Pósitrons , Humanos , Racloprida , Tempo de Reação , Tomografia por Emissão de Pósitrons/métodos , Exercício Físico , Neurotransmissores
9.
Nat Commun ; 15(1): 59, 2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167691

RESUMO

The dopaminergic system is firmly implicated in reversal learning but human measurements of dopamine release as a correlate of reversal learning success are lacking. Dopamine release and hemodynamic brain activity in response to unexpected changes in action-outcome probabilities are here explored using simultaneous dynamic [11C]Raclopride PET-fMRI and computational modelling of behavior. When participants encounter reversed reward probabilities during a card guessing game, dopamine release is observed in associative striatum. Individual differences in absolute reward prediction error and sensitivity to errors are associated with peak dopamine receptor occupancy. The fMRI response to perseverance errors at the onset of a reversal spatially overlap with the site of dopamine release. Trial-by-trial fMRI correlates of absolute prediction errors show a response in striatum and association cortices, closely overlapping with the location of dopamine release, and separable from a valence signal in ventral striatum. The results converge to implicate striatal dopamine release in associative striatum as a central component of reversal learning, possibly signifying the need for increased cognitive control when new stimuli-responses should be learned.


Assuntos
Dopamina , Estriado Ventral , Humanos , Reversão de Aprendizagem/fisiologia , Corpo Estriado/diagnóstico por imagem , Racloprida , Neostriado , Estriado Ventral/diagnóstico por imagem , Recompensa
10.
J Cereb Blood Flow Metab ; 44(3): 434-445, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-37882727

RESUMO

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.


Assuntos
Anfetamina , Dopamina , Feminino , Ratos , Animais , Anfetamina/farmacologia , Anfetamina/metabolismo , Racloprida/farmacocinética , Dopamina/metabolismo , Ratos Sprague-Dawley , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/metabolismo , Corpo Estriado/metabolismo
11.
Hum Brain Mapp ; 44(18): 6552-6560, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37950852

RESUMO

Feeding induces dopamine release in the striatum, and a dysfunction of the dopaminergic reward system can lead to overeating, and obesity. Studies have reported inconsistent findings of dopamine receptor (DR) positron emission tomography scans in obesity. Here we investigated the association between DR availability and overweight/obesity using Bayesian and frequentist meta-analysis. We performed a systematic search of Embase, Medline, Scopus and Web of Science for studies that compared striatal DR availability between lean subjects and overweight/obese subjects. The standardized mean difference (Hedge's g) of DR availability was calculated after extraction of data from each study. Studies were divided into two groups according to the definition of overweight/obese subjects (body mass index [BMI] cutoff of 25 and 30 kg/m2 ). Both Bayesian and frequentist meta-analysis was done in R Statistical Software version 4.2.2 (The R Foundation for Statistical Computing). Nine studies were eligible for inclusion in this study. Three studies with C11-raclopride, one with C11-PNHO, two with F18-fallypride, one with I123-IBZM, one with C11-NMB and one with both C11-raclopride and C11-PNHO were included. In Bayesian meta-analysis, the standardized mean difference of DR availability between lean and overweight/obese subjects markedly overlapped with zero regardless of BMI cutoff for obesity. In frequentist meta-analysis, the pooled standardized mean difference of DR availability did not show the significant difference between lean and overweight/obese subjects. There was an effect of the radiopharmaceutical on the standardized mean difference of DR availability in meta-analysis of BMI cutoff of 25 kg/m2 . In conclusion, brain DR availability is not different between lean and overweight/obese subjects. However, the effect is dependent on the radiopharmaceutical and the degree of obesity. Further studies with multi-radiopharmaceutical in the same individuals are needed to understand the association between DR and obesity.


Assuntos
Sobrepeso , Compostos Radiofarmacêuticos , Humanos , Racloprida/farmacologia , Teorema de Bayes , Receptores de Dopamina D2/metabolismo , Obesidade/diagnóstico por imagem , Encéfalo/metabolismo , Dopamina , Índice de Massa Corporal
12.
Neuroimage ; 283: 120416, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37866759

RESUMO

While all reversible receptor-targeting radioligands for positron emission tomography (PET) can be displaced by competition with an antagonist at the receptor, many radiotracers show limited occupancies using agonists even at high doses. [11C]Raclopride, a D2/D3 receptor radiotracer with rapid kinetics, can identify the direction of changes in the neurotransmitter dopamine, but quantitative interpretation of the relationship between dopamine levels and radiotracer binding has proven elusive. Agonist-induced receptor desensitization and internalization, a homeostatic mechanism to downregulate neurotransmitter-mediated function, can shift radioligand-receptor binding affinity and confound PET interpretations of receptor occupancy. In this study, we compared occupancies induced by amphetamine (AMP) in drug-naive wild-type (WT) and internalization-compromised ß-arrestin-2 knockout (KO) mice using a within-scan drug infusion to modulate the kinetics of [11C]raclopride. We additionally performed studies at 3 h following AMP pretreatment, with the hypothesis that receptor internalization should markedly attenuate occupancy on the second challenge, because dopamine cannot access internalized receptors. Without prior AMP treatment, WT mice exhibited somewhat larger binding potential than KO mice but similar AMP-induced occupancy. At 3 h after AMP treatment, WT mice exhibited binding potentials that were 15 % lower than KO mice. At this time point, occupancy was preserved in KO mice but suppressed by 60 % in WT animals, consistent with a model in which most receptors contributing to binding potential in WT animals were not functional. These results demonstrate that arrestin-mediated receptor desensitization and internalization produce large effects in PET [11C]raclopride occupancy studies using agonist challenges.


Assuntos
Dopamina , Receptores de Dopamina D3 , Camundongos , Animais , Receptores de Dopamina D3/metabolismo , Racloprida/farmacologia , Racloprida/metabolismo , Dopamina/metabolismo , Antagonistas de Dopamina , Arrestina/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Agonistas de Dopamina/farmacologia , Anfetaminas , Anfetamina/farmacologia
13.
Behav Brain Res ; 454: 114649, 2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37643667

RESUMO

Dopamine levels in the dorsomedial striatum (DMS) are highly dynamic and are thought to underly the encoding of action-outcome associations. Although it is known that amphetamine disrupts the learning that is required for goal-directed action, the role of D1 and D2 receptors in this process has not been established. In this study, we examined the role of D1 and D2 receptor antagonists on learning in response to amphetamine. We used the outcome-specific devaluation task to examine goal-directed action in male C57BL6/J mice treated systemically with either a D1 antagonist (SCH-23990; 0.01 mg/kg) or a D2 antagonist (raclopride; 0.5 mg/kg) and then administered amphetamine (1 mg/kg). The mice were injected repeatedly throughout the instrumental training phase of the task to assess the impact on the learning of action-outcomes, and the subsequent choice test assessing performance of goal-directed action was conducted drug free. Effects of chronic drug administration on locomotor behaviour was assessed before and after the choice test. Treatment during learning with either amphetamine, or the D1 or D2 antagonists, impaired the subsequent performance of goal-directed action. The amphetamine-induced impairment in goal-directed action was reversed in mice treated with raclopride, but not when treated with SCH-23990. By contrast, amphetamine-induced hyperactivity was reversed in mice treated with SCH-23990, but not in mice treated with raclopride. Taken together, these data support the role of a balance of dopamine receptor signalling after amphetamine treatment. While overall D1 receptor availability is necessary to promote learning, in a state of elevated dopamine, modifying D2 receptor function can ameliorate learning deficits.


Assuntos
Anfetamina , Dopamina , Masculino , Animais , Camundongos , Anfetamina/farmacologia , Racloprida/farmacologia , Condicionamento Clássico , Camundongos Endogâmicos C57BL , Receptores de Dopamina D2
14.
Psychiatry Res Neuroimaging ; 333: 111660, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37301129

RESUMO

BACKGROUND: Anhedonia is hypothesized to be associated with blunted mesocorticolimbic dopamine (DA) functioning in samples with major depressive disorder. The purpose of this study was to examine linkages between striatal DA, reward circuitry functioning, anhedonia, and, in an exploratory fashion, self-reported stress, in a transdiagnostic anhedonic sample. METHODS: Participants with (n = 25) and without (n = 12) clinically impairing anhedonia completed a reward-processing task during simultaneous positron emission tomography and magnetic resonance (PET-MR) imaging with [11C]raclopride, a DA D2/D3 receptor antagonist that selectively binds to striatal DA receptors. RESULTS: Relative to controls, the anhedonia group exhibited decreased task-related DA release in the left putamen, caudate, and nucleus accumbens and right putamen and pallidum. There were no group differences in task-related brain activation (fMRI) during reward processing after correcting for multiple comparisons. General functional connectivity (GFC) findings revealed blunted fMRI connectivity between PET-derived striatal seeds and target regions in the anhedonia group. Associations were identified between anhedonia severity and the magnitude of task-related DA release to rewards in the left putamen, but not mesocorticolimbic GFC. CONCLUSIONS: Results provide evidence for reduced striatal DA functioning during reward processing and blunted mesocorticolimbic network functional connectivity in a transdiagnostic sample with clinically significant anhedonia.


Assuntos
Transtorno Depressivo Maior , Dopamina , Humanos , Racloprida , Dopamina/metabolismo , Anedonia , Tomografia por Emissão de Pósitrons , Imageamento por Ressonância Magnética
15.
Neuropsychopharmacology ; 48(10): 1436-1445, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37349473

RESUMO

Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [18F]FECNT, and D2/D3R availability, with [11C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiple fixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days. We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use.


Assuntos
Cocaína , Tomografia por Emissão de Pósitrons , Haplorrinos , Animais , Feminino , Tomografia por Emissão de Pósitrons/métodos , Proteínas da Membrana Plasmática de Transporte de Dopamina , Receptores de Dopamina D3 , Cocaína/administração & dosagem , Cocaína/efeitos adversos , Autoadministração , Racloprida
16.
Cereb Cortex ; 33(13): 8485-8495, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37160338

RESUMO

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women's hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women's health.


Assuntos
Anticoncepcionais , Dopamina , Masculino , Animais , Humanos , Feminino , Racloprida , Dopamina/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D2/metabolismo , Cognição
17.
J Cereb Blood Flow Metab ; 43(7): 1206-1215, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36912083

RESUMO

The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [11C]PE2I (n = 20) and [18F]FE-PE2I (n = 20) and the D2/3 tracer [11C]raclopride (n = 18). Subjects with a [11C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [11C]DASB. Binding potential (BPND) and relative tracer delivery (R1) values were calculated on regional and voxel-level. Striatal R1 and BPND values were correlated, using either an MRI-based volume of interest (VOI) or an isocontour VOI based on the parametric BPND image. An inter-tracer comparison between [11C]PE2I BPND and [11C]DASB R1 was done on a VOI-level and simulations were performed to investigate whether the constraints of the modeling could cause correlation of the parameters. A positive association was found between BPND and R1 for all three dopamine tracers. A similar correlation was found for the inter-tracer correlation between [11C]PE2I BPND and [11C]DASB R1. Simulations showed that this relationship was not caused by cross-correlation between parameters in the kinetic model. In conclusion, these results suggest an association between resting-state striatal dopamine function and relative blood flow in healthy subjects.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Dopamina , Humanos , Racloprida , Estudos Retrospectivos , Tomografia por Emissão de Pósitrons/métodos , Circulação Cerebrovascular
19.
Commun Biol ; 6(1): 166, 2023 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-36765261

RESUMO

Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate's brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [11C]raclopride's binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [11C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of "high". We show for the first time that the "high" is associated with the fast dopamine increases induced by methylphenidate.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Metilfenidato , Humanos , Metilfenidato/farmacologia , Dopamina/metabolismo , Racloprida/metabolismo , Racloprida/farmacologia , Racloprida/uso terapêutico , Encéfalo/metabolismo , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico
20.
Addiction ; 118(6): 1053-1061, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36710462

RESUMO

BACKGROUND AND AIMS: Whereas striatal dopamine D2 receptor (D2R) availability has shown to be altered in individuals with alcohol use disorder (AUD) and in healthy individuals with a family history of AUD, the role of D2R in the development of AUD is unknown. In this positron emission tomography (PET) study, we measured whether D2R availability is associated with subsequent alcohol use and alcohol-related factors, at a follow-up 8 to 16 years post-PET scan, in social drinkers. DESIGN: Longitudinal study investigating the association between PET data and later self-report measures in healthy individuals. SETTING: Academic research imaging centre in Stockholm, Sweden. PARTICIPANTS: There were 71 individuals (68 of whom had evaluable PET data, 5 females, 42.0 years mean age) from a series of previous PET studies. MEASUREMENTS: One PET examination with the D2R antagonist radioligand [11 C]raclopride at baseline and self-report measures assessing alcohol use, drug use, impulsivity, reward sensitivity and family history of alcohol or substance use disorder at follow-up. FINDINGS: We found no evidence for an association between D2R availability and later alcohol use (B = -0.019, B 95% CI = -0.043 to -0.006, P = 0.147) nor for the majority of the alcohol-related factors (B 95% CI = -0.034 to 0.004, P = 0.273-0.288). A negative association with a small effect size was found between D2R availability and later impulsivity (B = -0.017, B 95% CI = -0.034 to -0.001, P = 0.046). CONCLUSIONS: Low striatal dopamine D2 receptor availability may not be a strong predictor in the development of alcohol use disorder.


Assuntos
Consumo de Bebidas Alcoólicas , Alcoolismo , Corpo Estriado , Receptores de Dopamina D2 , Feminino , Humanos , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/diagnóstico por imagem , Alcoolismo/genética , Alcoolismo/metabolismo , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Etanol , Estudos Longitudinais , Tomografia por Emissão de Pósitrons/métodos , Racloprida/farmacologia , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/metabolismo , Masculino , Adulto , Antagonistas dos Receptores de Dopamina D2/farmacologia , Seguimentos
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