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BACKGROUND: Magnetic resonance imaging (MRI) is used to diagnose and monitor disease activity in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to explore the association of "ultrabright" axial fluid-attenuated inversion recovery (FLAIR) lesions with gadolinium enhancement in patients with RRMS using qualitative and quantitative approaches. METHODS: MRIs from patients with RRMS from 2010 to 2015 were reviewed. Two radiologists independently identified ultrabright lesions on axial FLAIR sequences. The contrast-to-noise ratio (CNR) was measured for ultrabright and control lesions. RESULTS: Of 301 lesions included in the study, 77 (26%) were identified by both radiologists as ultrabright. Interrater agreement was moderate (κ = 0.77, P < .001). Lesions identified by both radiologists as ultrabright demonstrated an association with gadolinium enhancement (χ21 = 30.8, P < .001) but were not associated with MRI magnet strength (χ21 = 0.24, P = .65). Higher CNR values were associated with gadolinium enhancement for 1.5-T studies (OR, 1.05; 95% CI, 1.02-1.07; P = .001) and 3-T studies (OR, 1.02; 95% CI, 1.02-1.03; P < .001). Diagnostic accuracy of the quantitative model was good for 1.5-T studies (area under the curve, 0.79; 95% CI, 0.68-0.9; P < .001) and 3-T studies (area under the curve, 0.78; 95% CI, 0.73-0.84; P < .001). Positive predictive value of 100% was obtained for CNR values of 92 for 1.5-T and 184 for 3-T studies. CONCLUSIONS: Qualitatively and quantitatively identified ultrabright axial FLAIR lesions are significantly associated with gadolinium enhancement.
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RATIONALE: The endocannabinoid system is composed of endocannabinoids (such as anandamide), their target receptors (CB1 and CB2 receptors, CB1Rs and CB2Rs), the enzymes that degrade them (fatty-acid-amide-hydrolase (FAAH) for anandamide), and an endocannabinoid transporter. FAAH inhibition has been recently identified as having a critical involvement in behaviors related to nicotine addiction and has been shown to reduce the effect of nicotine on the mesolimbic dopaminergic system via CB1R and peroxisome proliferator-activated receptor alpha (PPARα). Thus, inhibition of FAAH may represent a novel strategy for smoking cessation, but its mechanism of action on relapse to nicotine seeking is still unknown. OBJECTIVE: The study aims to explore the mechanism of action of the inhibitor of FAAH activity, URB597, on relapse to nicotine seeking by evaluating the effect of the CB1R, CB2R, and PPARα antagonists on the attenuating effect of URB597 on cue-induced reinstatement of nicotine seeking in rats. RESULTS: URB597 reduced cue-induced reinstatement of nicotine seeking, an effect that was reversed by the CB1R antagonist rimonabant, but not by the CB2R or PPARα antagonists AM630 and MK886, respectively. CONCLUSIONS: These results indicate that URB597 reduces cue-induced reinstatement in rats through a CB1 receptor-dependent mechanism, and not via CB2R or PPARα. Since FAAH inhibition represent a novel and promising strategy for tobacco smoking cessation, dissecting how it produces its action may lead to a better understanding of the neurobiological mechanisms underlying nicotine addiction.
Assuntos
Amidoidrolases/antagonistas & inibidores , Benzamidas/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Carbamatos/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Nicotina/administração & dosagem , Receptor CB1 de Canabinoide/antagonistas & inibidores , Tabagismo/tratamento farmacológico , Amidoidrolases/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Sinais (Psicologia) , Endocanabinoides/metabolismo , Masculino , PPAR alfa/metabolismo , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Pirazóis/farmacologia , Ratos , Ratos Long-Evans , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , RimonabantoRESUMO
Varenicline, a nicotinic partial agonist, is the most effective treatment for tobacco use disorder. However, its mechanism of action is still unclear and may involve stimulating dopaminergic transmission. Here we used PET imaging with [(11)C]-(+)-PHNO to explore for the first time the impact of varenicline on dopamine transmission in the D2-rich striatum and D3-rich extra-striatal regions and its relationship with craving, withdrawal and smoking. Eleven treatment-seeking smokers underwent two PET scans with [(11)C]-(+)-PHNO, each following 12-h overnight smoking abstinence both prior to receiving varenicline and following 10-11 days of varenicline treatment (ie, at steady-state drug levels). Subjective measures of craving and urges to smoke were also assessed on the days of the PET scans. Varenicline treatment significantly reduced [(11)C]-(+)-PHNO binding in the dorsal caudate (p=0.008) and reduced some craving measures. These findings provide the first evidence that varenicline is able to increase DA levels in the human brain, a factor that may contribute to its therapeutic efficacy.
Assuntos
Química Encefálica/efeitos dos fármacos , Dopamina/análise , Fumar/terapia , Vareniclina/farmacologia , Adulto , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Química Encefálica/fisiologia , Dopamina/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/fisiologia , Receptores de Dopamina D3/efeitos dos fármacos , Receptores de Dopamina D3/fisiologia , Fumar/fisiopatologia , Dispositivos para o Abandono do Uso de TabacoRESUMO
There is considerable interest in blocking the dopamine D3 receptor (DRD3) versus the D2 receptor (DRD2) to treat drug addiction. However, there are currently no selective DRD3 antagonists available in the clinic. The anxiolytic drug buspirone has been proposed as a potential strategy as findings suggest that this drug has high in vitro affinity for DRD3, binds to DRD3 in brain of living non-human primate, and also disrupts psychostimulant self-administration in preclinical models. No study has explored the occupancy of DRD3 by buspirone in humans. Here, we used positron emission tomography (PET) and the D3-preferring probe, [(11)C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (decreases [(11)C]-(+)-PHNO binding) the DRD3 more readily than the DRD2. Eight healthy participants underwent [(11)C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60, and 120 mg of buspirone in a single-blind within-subjects design. [(11)C]-(+)-PHNO binding in DRD2- and DRD3-rich areas was decreased by the highest (60-120 mg), but not the lowest (30 mg), doses of buspirone. The maximal occupancy obtained was ~25% in both areas. Plasma levels of prolactin (a DRD2 marker) correlated with percentage occupancy after orally administered buspirone. Self-reported dizziness and drowsiness increased after buspirone but that did not correlate with receptor occupancy in any region. Overall, the modest occupancy of DRD2 and DRD3 even at high acute doses of buspirone, yielding high levels of metabolites, suggests that buspirone may not be a good drug to preferentially block DRD3 in humans.
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Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Buspirona/farmacologia , Dopaminérgicos/farmacologia , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Administração Oral , Adulto , Encéfalo/diagnóstico por imagem , Buspirona/efeitos adversos , Buspirona/sangue , Radioisótopos de Carbono , Tontura/induzido quimicamente , Tontura/metabolismo , Dopaminérgicos/efeitos adversos , Dopaminérgicos/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas , Tomografia por Emissão de Pósitrons , Prolactina/sangue , Método Simples-Cego , Fases do Sono/efeitos dos fármacos , Fases do Sono/fisiologia , Adulto JovemRESUMO
Tumefactive demyelination refers to large focal demyelinating lesions in the brain, which can be mistaken for malignancy. In some patients, these lesions are monophasic with a self-limited course; however, other patients demonstrate recurrent disease with new tumefactive or non-tumefactive lesions, and a subsequent diagnosis of relapsing-remitting multiple sclerosis is not uncommon. Owing to the limited data available in the literature, many questions about the patterns and prognostic significance of recurrent tumefactive lesions remain unanswered. The current case report involves a patient who recovered from tumefactive demyelination and presented two years later with a new recurrent tumefactive lesion in the contralateral brain.
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Esclerose Múltipla Recidivante-Remitente/diagnóstico , Adulto , Meios de Contraste , Diagnóstico Diferencial , Glucocorticoides/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Recidiva , Tomografia Computadorizada por Raios XRESUMO
Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here, we used PET and [(11)C]-(+)-PHNO ([(11)C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [(11)C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [(11)C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [(11)C]-(+)-PHNO binding in D2 and D3-rich areas (-12.0 and -15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [(11)C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission.
Assuntos
Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D3/metabolismo , Fumar/metabolismo , Adulto , Radioisótopos de Carbono/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D3/biossíntese , Regulação para Cima/efeitos dos fármacos , Adulto JovemRESUMO
The presentation of drug-associated cues has been shown to elicit craving and dopamine release in the striatum of drug-dependent individuals. Similarly, exposure to tobacco-associated cues induces craving and increases the propensity to relapse in tobacco- dependent smokers. However, whether exposure to tobacco-associated cues elicits dopamine release in the striatum of smokers remains to be investigated. We hypothesized that presentation of smoking-related cues compared to neutral cues would induce craving and elevation of intrasynaptic dopamine levels in subregions of the striatum and that the magnitude of dopamine release would be correlated with subjective levels of craving in briefly abstinent tobacco smokers. Eighteen participants underwent two [(11)C]-(+)-PHNO positron emission tomography (PET) scans after one-hour abstinence period: one during presentation of smoking-associated images and one during presentation of neutral images. Smoking cues significantly increased craving compared to neutral cues on one, but not all, craving measures; however, this increase in craving was not associated with overall significant differences in [(11)C]-(+)-PHNO binding potential (BPND) (an indirect measure of dopamine release) between the two experimental conditions in any of the brain regions of interest sampled. Our findings suggest that presentation of smoking cues does not elicit detectable (by PET) overall increases in dopamine in humans after one-hour nicotine abstinence. Future research should consider studying smoking cue-induced dopamine release at a longer abstinence period, since recent findings suggest the ability of smoking-related cues to induce craving is associated with a longer duration of smoking abstinence.
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Encéfalo/metabolismo , Dopamina/metabolismo , Abandono do Hábito de Fumar , Fumar/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Síndrome de Abstinência a Substâncias/diagnóstico por imagem , Síndrome de Abstinência a Substâncias/metabolismo , Adulto JovemRESUMO
Multiple studies suggest a pivotal role of the endocannabinoid system in the regulation of the reinforcing effects of various substances of abuse. Different approaches have been used to modulate endocannabinoid neurotransmission including the use of endogenous cannabinoid anandamide reuptake inhibitors. Previously, the effects of one of them, N-(4-hydroxyphenyl)-arachidonamide (AM404), have been explored in rodents trained to self-administer ethanol and heroin, producing some promising results. Moreover, AM404 attenuated the development and reinstatement of nicotine-induced conditioned place preference (CPP). In this study, we used the nicotine intravenous self-administration procedure to assess the effects of intraperitoneal administration of 0, 1, 3 and 10 mg/kg AM404 on nicotine-taking and food-taking behaviors under fixed-ratio and progressive-ratio schedules of reinforcement, as well as on reinstatement of nicotine-seeking induced by nicotine priming and by presentation of nicotine-associated cues. The ability of AM404 to produce place preference was also evaluated. AM404 did not produce CPP and did not modify nicotine-taking and food-taking behaviors. In contrast, AM404 dose-dependently attenuated reinstatement of nicotine-seeking behavior induced by both nicotine-associated cues and nicotine priming. Our results indicate that AM404 could be a potential promising therapeutic option for the prevention of relapse to nicotine-seeking in abstinent smokers.
Assuntos
Ácidos Araquidônicos/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Nicotina/administração & dosagem , Animais , Ácidos Araquidônicos/administração & dosagem , Sinais (Psicologia) , Relação Dose-Resposta a Droga , Comportamento Alimentar/efeitos dos fármacos , Injeções Intraperitoneais , Masculino , Ratos , Ratos Long-Evans , Esquema de Reforço , Prevenção Secundária , AutoadministraçãoRESUMO
BACKGROUND AND PURPOSE: The endocannabinoid system appears to play a pivotal role in mediating the rewarding and reinforcing effects of nicotine. Recent studies have shown that the inhibition of fatty acid amide hydrolase (FAAH) attenuates reinstatement of nicotine-seeking induced by nicotine priming and nicotine-associated cues. FAAH hydrolyses the endogenous endocannabinoid anandamide, as well as other non-cannabinoid ligands such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). As OEA and PEA can attenuate both nicotine-taking and nicotine-seeking behaviour, the specific role of anandamide remains unclear. In this study, we have tested the selective anadamide uptake inhibitor, VDM11, which elevates anandamide levels without affecting levels of OEA/PEA, on nicotine-taking and nicotine-seeking behaviour. EXPERIMENTAL APPROACH: We used a nicotine intravenous self-administration model in rats to assess the effect of VDM11, given i.p., on nicotine taking using fixed and progressive ratio schedules of reinforcement as well as on reinstatement of nicotine-seeking induced by nicotine priming and nicotine-associated cues. KEY RESULTS: VDM11 did not affect levels of responding for nicotine under fixed-ratio and progressive-ratio schedules of reinforcement. In contrast, VDM11 dose-dependently attenuated reinstatement of nicotine-seeking behaviour induced by nicotine-associated cues and nicotine priming. CONCLUSIONS AND IMPLICATIONS: These results indicate that ligands elevating anandamide levels could have therapeutic value for preventing relapse into nicotine-seeking behaviour and should be tested in humans trying to quit smoking.