Ren J, Xu H, Choi J-K, Jenkins BG, Chen YI. Dopaminergic response to graded dopamine concentration elicited by four amphetamine doses. Synapse 63: 764-772

Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA.
Synapse (Impact Factor: 2.13). 09/2009; 63(9):764-72. DOI: 10.1002/syn.20659
Source: PubMed


We studied the metabolic responses to different DA concentrations elicited by four doses of D-amphetamine (AMPH, 0, 0.25, 0.5, 1.0, or 3.0 mg/kg). We compared the degree of DA release (via microdialysis) with striatal cAMP activity and whole brain maps of cerebral blood volume (rCBV) changes (via pharmacological MRI, phMRI). Results: AMPH increased DA release in the caudate/putamen (CPu) and cAMP activity in the CPu, nucleus accumbens (NAc), and medial prefrontal cortex (mPFC) in a linear dose-dependent manner (P < 0.0001). The cAMP data suggest that, postsynaptically, signal transduction induced by D1 receptor is stronger than that of D2 receptor at the higher doses (1-3 mg/kg). phMRI showed that, while higher doses of AMPH (3 mg/kg (n = 7) and 1 mg/kg (n = 6)) induced significant rCBV increases in the CPu and NAc, the degree of rCBV increase was much smaller with AMPH of 0.5 mg/kg (n = 6). In contrast, AMPH of 0.25 mg/kg (n = 8) induced significant rCBV decreases in the anteromedial CPu and NAc. The sign switch of rCBV in response to AMPH from low to high doses likely reflects the switching in the balance of D2/D3 stimulation vs. D1/D5 stimulation. In conclusion, degree of postsynaptic signal transduction is linearly correlated to the extracellular DA concentration. However, the presynaptic binding may dominate the overall DA innervation at the lower range of DA concentration.

Download full-text


Available from: Haibo Xu
  • Source
    • ") with 10 min baseline scanning, and 35 min scanning following intravenous injection of 0 (vehicle; n ¼ 3 per group) or 1 mg/kg (n ¼ 13 per group) D-amphetamine in saline (1 mg/ml). At this dose, D-amphetamine has been shown to induce robust hemodynamic activation responses (Schwarz et al, 2004) that correlate with extracellular dopamine levels (Ren et al, 2009). Immediately after MRI, animals were euthanized with pentobarbital (300 mg/kg, i.p.) and transcardially perfused with cold phosphate buffered saline (PBS) followed by 4% formaldehyde in PBS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Methylphenidate is a widely prescribed psychostimulant for treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents, which raises questions regarding its potential interference with the developing brain. In the present study, we investigated effects of 3 weeks oral methylphenidate (5 mg/kg) vs vehicle treatment on brain structure and function in adolescent (post-natal day [P]25) and adult (P65) rats. Following a 1-week washout period, we used multimodal magnetic resonance imaging (MRI) to assess effects of age and treatment on independent component analysis-based functional connectivity (resting-state functional MRI), D-amphetamine-induced neural activation responses (pharmacological MRI), gray and white matter tissue volumes and cortical thickness (postmortem structural MRI), and white matter structural integrity (postmortem diffusion tensor imaging (DTI)). Many age-related differences were found, including cortical thinning, white matter development, larger dopamine-mediated activation responses and increased striatal functional connectivity. Methylphenidate reduced anterior cingulate cortical network strength in both adolescents and adults. In contrast to clinical observations from ADHD patient studies, methylphenidate did not increase white matter tissue volume or cortical thickness in rat. Nevertheless, DTI-based fractional anisotropy was higher in the anterior part of the corpus callosum following adolescent treatment. Furthermore, methylphenidate differentially affected adolescents and adults as evidenced by reduced striatal volume and myelination upon adolescent treatment, although we did not observe adverse treatment effects on striatal functional activity. Our findings of small but significant age-dependent effects of psychostimulant treatment in the striatum of healthy rats highlights the importance of further research in children and adolescents that are exposed to methylphenidate.
    Full-text · Article · Jul 2013 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
  • Source
    • "Viewing DA-mediated function in terms of opposing D1 and D2 contributions helps explain some subtle features of data in domains of dose and time and reconciles some pronounced differences observed across species and versus drug dosages. Amphetamine stimulation in the rat produces pronounced increases in CBV except at very small doses, where responses become slightly negative, an effect that was attributed to the high affinity of DA for a subset of D2-like receptors (Ren et al., 2009). In the NeuroImage 75 (2013) 46–57 ⁎ Corresponding author. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine's effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET 11C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations.
    Full-text · Article · Mar 2013 · NeuroImage
  • Source
    • "This shift in DAergic activation has Fig. 5. Scatterplot of striatal D 2/3 binding ratios and the individual fit per subject to the time course of component 10 of the ICA. been shown to be dependent on the size of the dAMPH challenge administered (Ren et al., 2009). It seems likely that the response we found was dominated by D 1 -type receptor mediated effects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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 21.0 years (± 1.5) were included. We used a pseudo-continuous ASL sequence (40 minutes) to quantify cerebral blood flow (CBF) and started dAMPH infusion (0.3 mg/kg) after 10 minutes. On another day, we measured baseline dopamine D(2/3) 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 D(2/3) 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 D(2/3) receptor availability and behavioral measures. Our observations are in line with literature and provide further evidence that that ASL-based phMRI with dAMPH is a promising technique to assess DAergic function in human subjects.
    Full-text · Article · Jan 2013 · NeuroImage
Show more