Search

Thème : Architecture matérielles et logicielles; National audience

National audience

Gd-BOPTA (gadobenate dimeglumine) is a magnetic resonance (MR) contrast agent that, after i.v. administration, distributes within the extracellular space, enters rat hepatocytes through the sinusoidal transporters organic anion transporting peptides (Oatps) and is excreted unchanged into bile through the multidrug resistance-associated protein 2 (Mrp2). It is unclear how the hepatobiliary contrast agent would accumulate in cholestatic fatty livers from obese rats with bile flow impairment. Indeed, the expression of both Oatps and Mrp2 transporters is decreased in cholestatic hepatocytes. To assess this question, we measured on-line the hepatic concentrations of ¹⁵³Gd-BOPTA with a gamma probe placed over perfused rat livers. During the perfusion of ¹⁵³Gd-BOPTA, we obtained a similar maximal hepatic concentration in normal and fatty livers despite the decreased expression and function of membrane transporters in fatty livers. By pharmacokinetic modeling and mathematical simulations, we show how changes of transport into and out of hepatocytes modify the concentrations of ¹⁵³Gd-BOPTA within hepatocytes. Mathematical simulations help to understand how each parameter (entry into hepatocytes, bile excretion, or efflux back to sinusoids) interferes with the hepatic concentrations. The hepatic concentrations of ¹⁵³Gd-BOPTA within hepatocytes rely on the entry into hepatocytes through the sinusoidal membrane and on two paths of exit, the efflux back to sinusoids and the elimination into bile. Understanding how ¹⁵³Gd-BOPTA accumulates in hepatocytes is then complex. However, such understanding is important to analyze liver imaging with hepatobiliary contrast agents in cholestatic fatty livers.

Δ⁹-tetrahydrocannabinol (THC), through its action on cannabinoid type-1 receptor (CB₁R), is known to activate dopamine (DA) neurotransmission. Functional evidence of a direct antagonistic interaction between CB₁R and DA D₂-receptors (D₂R) suggests that D₂R may be an important target for the modulation of DA neurotransmission by THC. The current study evaluated, in rodents, the effects of chronic exposure to THC (1 mg/kg/day; 21 days) on D₂R and D₃R availabilities using the D₂R-prefering antagonist and the D₃R-preferring agonist radiotracers [¹⁸F]fallypride and [³H]-(+)-PHNO, respectively. At 24 h after the last THC dose, D₂R and D₃R densities were significantly increased in midbrain. In caudate/putamen (CPu), THC exposure was associated with increased densities of D₂R with no change in D₂R mRNA expression, whereas in nucleus accumbens (NAcc) both D₃R binding and mRNA levels were upregulated. These receptor changes, which were completely reversed in CPu but only partially reversed in NAcc and midbrain at 1 week after THC cessation, correlated with an increased functionality of D₂/₃R in vivo, based on findings of increased locomotor suppressive effect of a presynaptic dose and enhanced locomotor activation produced by a postsynaptic dose of quinpirole. Concomitantly, the observations of a decreased gene expression of tyrosine hydroxylase in midbrain together with a blunted psychomotor response to amphetamine concurred to indicate a diminished presynaptic DA function following THC. These findings indicate that the early period following THC treatment cessation is associated with altered presynaptic D₂/₃R controlling DA synthesis and release in midbrain, with the concurrent development of postsynaptic D₂/₃R supersensitivity in NAcc and CPu. Such D₂/₃R neuroadaptations may contribute to the reinforcing and habit-forming properties of THC.

International audience

Although mood disorders such as depression are better diagnosed, their treatment often remains unsatisfactory. Pharmacological treatments of depression mostly target the central monoaminergic systems, especially serotonergic transmission. Various adverse effects (e.g. weight gain, nausea, headache, constipation), the relative inefficiency of the treatments (response rate no more than 50–60%) as well as the delay in the onset of therapeutic action represent some serious limitations. In addition to the improvement of selectivity of molecules available on the market and a better understanding of their mechanisms of action, other neurotransmitter systems that have received little attention so far are now being targeted for the treatment of depression. Glutamate receptor antagonists (e.g. ketamine, traxoprodil), nicotinic modulators (e.g. mecamylamine, varenicline), atypical antipsychotics (e.g. aripiprazole, quetiapine) possess antidepressant activity. The focus of the proposed research is to review recent developments in this field and the new prospects that it opens.

Elderly individuals display a rapid age-related increase in intraindividual variability (IIV) of their performances. This phenomenon could reflect subtle changes in frontal lobe integrity. However, structural studies in this field are still missing. To address this issue, we computed an IIV index for a simple reaction time (RT) task and performed magnetic resonance imaging (MRI) including voxel based morphometry (VBM) and the tract based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) in 61 adults aged from 22 to 88 years. The age-related IIV increase was associated with decreased fractional anisotropy (FA) as well as increased radial (RD) and mean (MD) diffusion in the main white matter (WM) fiber tracts. In contrast, axial diffusion (AD) and grey matter (GM) densities did not show any significant correlation with IIV. In multivariate models, only FA has an age-independent effect on IIV. These results revealed that WM but not GM changes partly mediated the age-related increase of IIV. They also revealed that the association between WM and IIV could not be only attributed to the damage of frontal lobe circuits but concerned the majority of interhemispheric and intrahemispheric corticocortical connections.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are in vivo tracer kinetic techniques that employ specific, venously injected radiotracers to image molecular interactions and pathways. PET and SPECT imaging processes involve multiple steps, including radionuclide production, radiosynthesis, preclinical imaging, signal and image processing and, ultimately, clinical application. These technologies provide quantitative information about physiological and biological properties, such as cerebral blood flow, glucose metabolism and receptor concentration, that have the potential to answer a large number of important clinical questions. However, the raw data obtained by PET and SPECT do not correspond directly to the biological parameters of interest, but instead represent variations in tracer concentrations and states in tissue. Post-processing is therefore required to accurately transform this raw information into an interpretable form. This is accomplished using tracer kinetic models that simulate the kinetic behavior of the radioactive tracer, expressed in terms of functional compartments represented by mathematical expressions. This thesis explores the mathematical modeling of neurotransmitter systems in the human and rat brain using PET and SPECT, and its application to parametric imaging. The main goal was to propose reliable and simple methods for extracting biological parameter values for a given brain region or for the brain as a whole to build parametric images. We have firstly shown that benzodiazepine receptor concentration and ligand affinity could be obtained using a non-invasive and very simple protocol that is appropriate for routine clinical use. This development highlighted the importance of modeling in PET and SPECT, particularly for brain receptor imaging. For example, we have shown that both 11C-labeled flumazenil ([11C]FMZ) and 123I-labeled iomazenil ([123I]IMZ) could be used to map benzodiazepine receptor distribution, but each required different experimental protocols that depended mainly on the kinetic properties of the injected tracer. A new approach is then proposed to study tracer kinetics using SPECT data. This new method, termed the dual-ligand approach, uses an adaptation of the multi-injection protocol and enables all model binding parameters to be measured with acceptable standard errors. Modeling is then applied to the entire SPECT (or PET) dataset to build parametric images at the pixel level. The proposed modeling method is based on the application of wavelet filtering to dynamic data. This work, which represents the first attempt proposed in the literature to improve the signal-to-noise ratio using a wavelet filtering method, provides a theoretical framework for analyzing data and presents an initial application of PET and SPECT to imaging of biological parameters at the whole brain level. In the next section, imaging techniques are used to evaluate quantitative protocols in the rat. Here, we have used the β-microprobe, which, because of its high temporal and spatial resolution, is an appropriate tool for kinetic analysis, and the YAP-(S)PET system, which is a dedicated small-animal scanner for the non-invasive analysis of radioligand distribution in the whole brain. Using 2-deoxy-2-18F-fluoro-D-glucose ([18F]FDG) and the 18F-labeled 5-HT1A receptor antagonist, [18F]MPPF, to assess glucose consumption and 5-HT1A receptors, respectively, we found that the β-microprobe was suitable for quantitative studies, but some correction factors should be included with YAP-(S)PET data to improve quantitative results.