RESUMEN
D-amphetamine (dAMPH) and methylphenidate (MPH) are stimulants used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Preclinical studies have shown that in healthy animals, dAMPH induces dopamine (DA) dysfunction, as evidenced for instance by loss of DA levels and its transporters. It has also been suggested that DA plays an important role in emotional processing, and that altered DA-ergic intervention may modulate amygdala function. To explore the role of the DA system in emotional processing we examined emotional processing using functional magnetic resonance imaging (fMRI) in eight male recreational users of dAMPH and eight male healthy controls. We compared brain activation between both groups during an emotional face-processing task with and without an oral MPH challenge. All subjects were abstinent for at least 2 weeks during the baseline scan. The second scan was performed on the same day 1½ hours after receiving an oral dose of 35 mg MPH. A significant Valence*Group interaction (p = .037) indicated amygdala hyperreactivity to fearful facial expressions in dAMPH users that was robust against adjustment for age (p = .015). Furthermore, duration of amphetamine use in years was positively correlated with amygdala reactivity in dAMPH users (r = .76; p = .029). These exploratory findings are in line with previous findings suggesting that DA plays a role in emotional processing.
Asunto(s)
Trastornos Relacionados con Anfetaminas/fisiopatología , Encéfalo/efectos de los fármacos , Inhibidores de Captación de Dopamina/administración & dosificación , Reconocimiento Facial/efectos de los fármacos , Metilfenidato/administración & dosificación , Administración Oral , Adulto , Trastornos Relacionados con Anfetaminas/psicología , Encéfalo/fisiopatología , Mapeo Encefálico , Emociones/efectos de los fármacos , Emociones/fisiología , Reconocimiento Facial/fisiología , Humanos , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiopatología , Pruebas Neuropsicológicas , Estimulación Luminosa , Tiempo de Reacción , Adulto JovenRESUMEN
Preclinical studies suggest that dexamphetamine (dAMPH) can lead to monoaminergic neurotoxicity. This exploratory study aimed to investigate effects of recreational dAMPH use on the dopamine (DA) and noradrenaline (NA) systems in humans. To that purpose, eight male abstinent dAMPH (26.0 ± 4.0 years) users and 10 age- and IQ-matched male healthy control subjects (23.0 ± 3.8) underwent neuropsychological testing sensitive to DAergic function and single photon emission computed tomography (SPECT) scanning with [(123)I]FP-CIT to determine striatal DA transporter (DAT) binding. In addition, changes in cerebral blood flow (CBF) induced by the DA/NA reuptake inhibitor methylphenidate (MPH) were measured using pharmacological magnetic resonance imaging (phMRI). Performance of dAMPH users was significantly worse on executive function and verbal memory tasks. Striatal DAT binding ratios were on average lower in dAMPH users (near-significant, p=0.05). In addition, CBF in control subjects decreased significantly in response to MPH in gray matter and basal ganglia, among which the striatum, thalamus and hippocampus by 10% to 29%. However, in dAMPH users the CBF response was blunted in most brain areas studied, only decreasing in the hippocampus and orbitofrontal cortex. When comparing groups, CBF response was found to be significantly different in the thalamus with a decrease for healthy controls and a blunted response in dAMPH users. Collectively, our findings of a blunted hemodynamic response in monoaminergic regions, in combination with indications for lower striatal DAT binding and poorer behavioral measures are likely to represent DAergic dysfunction in dAMPH users, although NAergic dysfunction may also play a role.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Dextroanfetamina/efectos adversos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Consumidores de Drogas/psicología , Adulto , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Función Ejecutiva/efectos de los fármacos , Neuroimagen Funcional , Humanos , Radioisótopos de Yodo , Masculino , Memoria/efectos de los fármacos , Metilfenidato/farmacología , Pruebas Neuropsicológicas , Cintigrafía , TropanosRESUMEN
Pharmacological magnetic resonance imaging (phMRI) maps the neurovascular response to a pharmacological challenge and is increasingly used to assess neurotransmitter systems. Here we investigated the hemodynamic response to a dopaminergic (DAergic) challenge with dextroamphetamine (dAMPH) in humans using arterial spin labeling (ASL) based phMRI. Twelve healthy male subjects aged 21.0years (±1.5) were included. We used a pseudo-continuous ASL sequence (40min) to quantify cerebral blood flow (CBF) and started dAMPH infusion (0.3mg/kg) after 10min. On another day, we measured baseline dopamine D2/3 receptor availability with [(123)I]IBZM single photon emission computed tomography (SPECT). Baseline measures on mood and impulsivity and subjective behavioral responses to dAMPH were obtained. CBF response was corrected for cardiovascular effects using an occipital cortex mask for internal reference. Corrected CBF (sCBF) was analyzed using ROI-based and voxel-based analysis, in addition to independent component analysis (ICA). CBF data was correlated to D2/3 receptor availability and behavioral measures. Subjects reported experiencing euphoria following dAMPH administration. In the striatum sCBF significantly increased, as demonstrated by all three analysis methods. Voxel-based analysis and ICA also showed increased sCBF in the thalamus, anterior cingulate and cerebellum. Decreased sCBF was observed in several cortical areas, the posterior cingulated and paracingulate cortex. Apart from one ICA component, no correlations were found with sCBF changes and D2/3 receptor availability and behavioral measures. Our observations are in line with literature and provide further evidence that ASL-based phMRI with dAMPH is a promising technique to assess DAergic function in human subjects.
Asunto(s)
Mapeo Encefálico/métodos , Encéfalo/irrigación sanguínea , Estimulantes del Sistema Nervioso Central/farmacología , Dextroanfetamina/farmacología , Dopamina/metabolismo , Imagen por Resonancia Magnética/métodos , Encéfalo/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Hemodinámica , Humanos , Masculino , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Marcadores de Spin , Tomografía Computarizada de Emisión de Fotón Único , Adulto JovenRESUMEN
BACKGROUND: Dopamine (DA) is involved in systems governing motor actions, motivational processes and cognitive functions. Preclinical studies have shown that even relatively low doses of d-amphetamine (dAMPH) (equivalent to doses used in clinical Practice) can lead to DA neurotoxicity in rodents and non-human primates (Ricaurte et al., 2005). METHODS: Therefore, we investigated the DAergic function in eight male recreational users of dAMPH and eight male healthy controls using functional magnetic resonance imaging (fMRI). We compared brain activation between both groups during a monetary incentive delay task (Knutson et al., 2001) with and without an oral methylphenidate (MPH) challenge. All subjects were abstinent for at least 2 weeks during the baseline scan. The second scan was performed on the same day 1.5 h after receiving an oral dose of 35 mg MPH (approximately 0.5 mg/kg) when peak MPH binding was assumed. RESULTS: When anticipating reward, dAMPH users showed lower striatal activation in comparison to control subjects. In addition, MPH induced a reduction in the striatal activation during reward anticipation in healthy controls, whereas no such effect was observed in dAMPH users. CONCLUSION: The combination of these findings provides further evidence for frontostriatal DAergic dysfunction in recreational dAMPH users and is consistent with preclinical data suggesting neurotoxic effects of chronic dAMPH use. The findings of this explorative study could have important implications for humans in need for treatment with dAMPH, such as patients suffering from ADHD and therefore this study needs replication in a larger sample.
Asunto(s)
Dextroanfetamina , Dopamina/metabolismo , Imagen por Resonancia Magnética/métodos , Metilfenidato/metabolismo , Motivación/fisiología , Recompensa , Adulto , Inhibidores de Captación de Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Humanos , Masculino , Metilfenidato/farmacología , Motivación/efectos de los fármacos , Estimulación Luminosa , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Adulto JovenRESUMEN
3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug that has been shown to induce loss of brain serotonin (5-HT) neurons. The purpose of this study was to determine the usefulness of pharmacological magnetic resonance imaging (phMRI) in assessing 5-HT dysfunction by examining the hemodynamic response evoked by infusion with the selective 5-HT reuptake inhibitor citalopram. We studied the effects of MDMA on brain hemodynamics using arterial spin labeling (ASL) based phMRI following a citalopram challenge (7.5mg/kg, i.v.), combined with [¹²³I]ß-CIT SPECT imaging in ten male MDMA users and seven healthy non-users. Single photon emission computed tomography (SPECT) imaging was used to assess the availability of 5-HT transporters (SERT). Imaging results were compared with the results of behavioral measures and mood changes following drug administration, in both groups (using the Beck Depression Inventory, Barratt Impulsiveness Scale and a visual analog scale). Reductions in SERT binding were observed in the occipital cortex of MDMA users. In line with this, citalopram induced decreases in cerebral blood flow (CBF) in the occipital cortex of MDMA users. ASL based phMRI also detected a CBF decrease in the thalamus of MDMA users. In concordance with imaging findings, behavioral measures differed significantly between MDMA users and controls. MDMA users had higher impulsivity scores and felt more uncomfortable after citalopram infusion, compared with control subjects. Our findings indicate that phMRI is very well suited for in-vivo assessment of 5-HT dysfunction.