In vivo imaging of dopamine receptors in a model of temporal lobe epilepsy

Department of Nuclear Medicine, University of Mainz, Mainz, Germany.
Epilepsia (Impact Factor: 4.57). 08/2009; 51(3):415-22. DOI: 10.1111/j.1528-1167.2009.02272.x
Source: PubMed


Alterations in dopamine neurotransmission in animal models of epilepsies have been frequently demonstrated using invasive neuroscience or ex vivo techniques. We aimed to test whether corresponding alterations could be detected by noninvasive in vivo brain imaging with positron emission tomography (PET) in the chronic phase of the rat pilocarpine model of temporal lobe epilepsy.
Six pilocarpine-treated Wistar rats exhibiting spontaneous recurrent seizures and nine control rats were studied with PET using [(18)F]-fallypride, a high-affinity dopamine D(2/3) receptor ligand. Parametric images of [(18)F]-fallypride specific binding were calculated using a reference tissue method, and the two groups were contrasted by whole-brain voxel-based analysis implemented in statistical parametric mapping (SPM5).
Dopamine D(2/3) receptor availability was 27% lower in the bilateral anterior caudate-putamen of pilocarpine-treated rats as compared to controls (p < 0.05), but binding was unaffected in other striatal or extrastriatal regions.
The finding of substantially reduced availability of dopamine D(2/3) receptors in the anterior caudate-putamen of rats during the chronic phase of the pilocarpine model is in agreement with results of invasive (microinjection, microdialysis) animal studies that have revealed increased dopamine tonus and a D(2/3) receptor-mediated anticonvulsant action of dopamine in the anterior segment of the rat striatum. The present PET approach could be prospectively applied for monitoring dopamine receptor changes longitudinally, that is, at different phases of the epileptogenic process, and opens perspectives for testing dopaminergic agents as potential antiepileptogenic drugs.

Download full-text


Available from: Erwan Dupont, Sep 22, 2014
  • Source
    • "In accordance with imaging studies performed in epileptic patients (Table 1), animal studies confirmed that reduced levels of D2R expression are detected in epileptogenic areas in seizing rodents. For example, D2-like binding sites were reduced in the caudate–putamen (CP) of pilocarpine-treated rats (Yakushev et al., 2010) and genetically epileptic GAERS (genetic absence epilepsy rat from Strasbourg; Jones et al., 2010) and WAG/Rij (Wistar Albino Glaxo rats from Rijswijk; Birioukova et al., 2005) rats. Interestingly, WAG/Rij rats also showed a reduced D2-like binding in the CA3 region, confirming a prominent role of D2R signaling in limbic epileptogenesis (Birioukova et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical and experimental studies implicate most neuromodulatory systems in epileptogenesis. The dopaminergic system has a seizure-modulating effect that crucially depends on the different subtypes of dopamine (DA) receptors involved and the brain regions in which they are activated. Specifically, DA plays a major role in the control of seizures arising in the limbic system. Studies performed in a wide variety of animal models contributed to illustrate the opposite actions of D1-like and D2-like receptor signaling in limbic epileptogenesis. Indeed, signaling from D1-like receptors is generally pro-epileptogenic, whereas D2-like receptor signaling exerts an anti-epileptogenic effect. However, this view might appear quite simplistic as the complex neuromodulatory action of DA in the control of epileptogenesis likely requires a physiological balance in the activation of circuits modulated by these two major DA receptor subtypes, which determines the response to seizure-promoting stimuli. Here we will review recent evidences on the identification of molecules activated by DA transduction pathways in the generation and spread of seizures in the limbic system. We will discuss the intracellular signaling pathways triggered by activation of different DA receptors in relation to their role in limbic epileptogenesis, which lead to the activation of neuronal death/survival cascades. A deep understanding of the signaling pathways involved in epileptogenesis is crucial for the identification of novel targets for the treatment of epilepsy.
    Frontiers in Cellular Neuroscience 09/2013; 7:157. DOI:10.3389/fncel.2013.00157 · 4.29 Impact Factor
  • Source
    • "Unlike postmortem analyses, in which observations are limited to specific time points following insults, in vivo studies can assess the evolution and resolution of brain processes over time. Several in vivo imaging studies have established the utility of the pilocarpine model for investigating the epileptogenesis of TLE (van Eijsden et al., 2004; Niessen et al., 2005; Kuo et al., 2008; Yakushev et al., 2010). Therefore, 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) can be used to monitor glucose metabolism in vivo, showing that interictal hypometabolism may be associated with the epileptic network. "
    [Show abstract] [Hide abstract]
    ABSTRACT:   The metabolic and biochemical changes that occur during epileptogenesis remain to be determined. (18) F-Fluorodeoxyglucose positron emission tomography (FDG-PET) and proton magnetic resonance spectroscopy ((1) H MRS) are noninvasive techniques that provide indirect information on ongoing pathologic changes. We, therefore, utilized these methods to assess changes in glucose metabolism and metabolites in the rat lithium-pilocarpine model of epilepsy as markers of epileptogenesis from baseline to chronic spontaneous recurrent seizures (SRS).   PET and MRS were performed at baseline, and during the acute, subacute, silent, and chronic periods after lithium-pilocarpine induced status epilepticus (SE). Sequential changes in glucose metabolism on (18) F-FDG PET using SPM2 and the ratios of percent injected dose per gram (%ID)/g of regions of interest (ROIs) in the bilateral amygdala, hippocampus, basal ganglia with the thalamus, cortex, and hypothalamus normalized to the pons were determined. Voxels of interest (VOIs) on (1) H MRS were obtained at the right hippocampus and the basal ganglia. NAA/Cr levels and Cho/Cr at various time points were compared to baseline values.   Of 81 male Sprague-Dawley rats, 30 progressed to SRS. (18) F-FDG PET showed widespread global hypometabolism during the acute period, returning to baseline level during the subacute period. Glucose metabolism, however, declined in part of the hippocampus during the silent period, with the hypometabolic area progressively expanding to the entire limbic area during the chronic period. (1) H MRS showed that the NAA/Cr levels in the hippocampus and basal ganglia were reduced during the acute period and were not restored subsequently from the subacute to the chronic period without any significant change in the Cho/Cr ratio throughout the entire experiment.   Serial metabolic and biochemical changes in the lithium-pilocarpine model of epilepsy indirectly represent the process of human epileptogenesis. Following initial irreversible neural damage by SE, global glucose metabolism transiently recovered during the subacute period without neuronal recovery. Progressive glucose hypometabolism in the limbic area during the silent and chronic periods may reflect the important role of the hippocampus in the formation of ongoing epileptic network during epileptogenesis.
    Epilepsia 03/2012; 53(5):860-9. DOI:10.1111/j.1528-1167.2012.03432.x · 4.57 Impact Factor
  • Source
    • "PET can effectively monitor the area that is responsible from epilepsy comas (Wagner, 1995). A research group (Yakushev et al. 2010) tried to image the brain of rat having epilepsy by PET. [ 18 F]-fallypride was used as a PET tracer which is highly specific to dopamine D2/3 receptor ligand on six rats treated with pilocarpine exhibiting spontaneous recurrent seizures and nine control . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Among different imaging modalities, Positron Emission Tomography (PET) gained importance in routine hospital practice depending on ability to diagnose diseases in early stages and tracing of therapy by obtaining metabolic information. The combination of PET with Computed Tomography (CT) forms hybrid imaging modality that gives chance to obtain better images having higher resolution by fusing both functional and anatomical images in the same imaging modality at the same time. Therefore, better contrast agents are essentially needed. The advance in research about developing drug delivery systems as specific nanosized targeted systems gained an additional importance for obtaining better diagnosis and therapy of different diseases. Liposomes appear to be more attractive drug delivery systems in delivering either drugs or imaging ligands to target tissue or organ of diseases with higher accumulation by producing in nano-scale, long circulating by stealth effect and specific targeting by modifying with specific ligands or markers. The combination of positron emitting radionuclides with liposomes are commonly in research level nowadays and there is no commercially available liposome formulation for PET imaging. However by conjugating positron emitter radionuclide with liposomes can form promising diagnostic agents for improved diagnosis and following up treatments by increasing image signal/contrast in the target tissue in lower concentrations by specific targeting as the most important advantage of liposomes. More accurate and earlier diagnosis of several diseases can be obtained even in molecular level with the use of stable and effectively radiolabeled molecular target specific nano sized liposomes with longer half-lived positron emitting radionuclides.
    Drug Delivery 01/2012; 19(1):68-80. DOI:10.3109/10717544.2011.635721 · 2.56 Impact Factor
Show more