Type of Anesthesia Influences Positron Emission Tomography Measurements of Dopamine D2/3 Receptor Binding in the Rat Brain

Rats are often anesthetized prior to positron emission tomography (PET) brain imaging in order to prevent head movements. Anesthesia can be administered by inhalation agents, such as isoflurane (Forene), or injection mixtures, such as fentanyl-fluanisone-midazolam (Hypnorm-Dormicum). Unfortunately, anesthesia affects a variety of physiological variables, including those in the brain. The aim of this study was to compare the effects of inhalation and injection anesthesia on the binding potential of the dopaminergic D2/3 tracer [11C]raclopride used for PET brain imaging in human and animal studies. Male Lewis rats were assigned to either inhalation (isoflurane; N=4) or injection (fentanyl-fluanisone-midazolam; N=5) anesthesia. Isoflurane was given continuously, and fentanyl-fluanisone-midazolam was supplemented every 30-60 minutes when the tail reflex was positive. Catheters were surgically placed in femoral arteries and veins for blood sampling and tracer injection. After a short attenuation scan, the rats were PET scanned for 90 minutes after injection of [11C]raclopride. We found that rats anesthetized with isoflurane had double the binding potential in the striatum compared with fentanyl-fluanisone-midazolam anesthetized rats. Our results are in agreement with other studies showing that anesthesia may have a major influence on brain imaging studies involving tracer kinetics in rats

Autoradiographic characterization of [18 F]PSMA-1007 binding in rat brain.

Carboxypeptidase II (CBPII) in brain metabolizes the neuroactive substance N-acetyl-L-aspartyl-L-glutamate (NAGG) to yield the elements of glutamate and N-acetyl-aspartate (NAA). In peripheral organs, CBPII is known as prostrate specific membrane antigen (PSMA), which presents an important target for nuclear medicine imaging in prostate cancer. Available PSMA ligands for PET imaging do not cross the blood-brain barrier, and there is scant knowledge of the neurobiology of CBPII, despite its implication in the regulation of glutamatergic neurotransmission. In this study we used the clinical PET tracer [18 F]-PSMA-1007 ([18 F]PSMA) for an autoradiographic characterization of CGPII in rat brain. Ligand binding and displacement curves indicated a single site in brain, with KD of about 0.5 nM, and Bmax ranging from 9 nM in cortex to 19 nM in white matter (corpus callosum and fimbria) and 24 nM in hypothalamus. The binding properties of [18 F]PSMA in vitro should enable its use for autoradiographic investigations of CBPII expression in animal models of human neuropsychiatric conditions

PET radioligand injection for pig neuroimaging

Pigs are useful models in neuroimaging studies with positron emission tomography (PET). Radiolabeled ligands are injected intravenously at the start of the scan and in pigs the most easily accessible route of administration is the ear vein. However, in brain studies the short distance between the brain and ear vein can be problematic as both are localized inside the field of view and, as a consequence, tracer residues in the catheter may influence the outcome of the scan. Here, we discuss options to avoid this problem. The femoral vein can be used in studies where repeated arterial blood sampling is needed because surgical incision has to be performed to allow access to the artery. When a non-invasive technique is preferred, the ear vein is a good alternative although it is recommended to dilute the tracer sufficiently in saline (20-50 mL) prior to injection. In addition, the tracer can be injected through an extension tube (filled with saline before injection), which is removed together with the syringe immediately after tracer injection. This avoids placing the syringe with tracer inside the PET gantry while injecting. By applying these simple techniques, it is our experience that it is possible to obtain high-quality images without exposing pigs to invasive procedures

Radioligand binding analysis of α₂ adrenoceptors with [¹¹C]yohimbine in brain in vivo:Extended Inhibition Plot correction for plasma protein binding

Abstract We describe a novel method of kinetic analysis of radioligand binding to neuroreceptors in brain in vivo, here applied to noradrenaline receptors in rat brain. The method uses positron emission tomography (PET) of [11C]yohimbine binding in brain to quantify the density and affinity of α 2 adrenoceptors under condition of changing radioligand binding to plasma proteins. We obtained dynamic PET recordings from brain of Spraque Dawley rats at baseline, followed by pharmacological challenge with unlabeled yohimbine (0.3 mg/kg). The challenge with unlabeled ligand failed to diminish radioligand accumulation in brain tissue, due to the blocking of radioligand binding to plasma proteins that elevated the free fractions of the radioligand in plasma. We devised a method that graphically resolved the masking of unlabeled ligand binding by the increase of radioligand free fractions in plasma. The Extended Inhibition Plot introduced here yielded an estimate of the volume of distribution of non-displaceable ligand in brain tissue that increased with the increase of the free fraction of the radioligand in plasma. The resulting binding potentials of the radioligand declined by 50–60% in the presence of unlabeled ligand. The kinetic unmasking of inhibited binding reflected in the increase of the reference volume of distribution yielded estimates of receptor saturation consistent with the binding of unlabeled ligand

From Individual to Collective Pinning: Effect of Long-range Elastic Interactions

We study the effect of long-range elastic interactions in the dynamical behavior of an elastic chain driven quasi-statically in a quenched random pinning potential and in the strong pinning limit. This is a generic situation occuring in solid friction, crack propagation, wetting front motion, ... Tuning the exponent of the algebraic decay of the elastic interaction with the distance is shown to give rise to three regimes: a Mean-Field (MF) regime, a Laplacian (L) regime and an intermediate regime where the critical exponents interpolate continuously between the MF and L limit cases. The effect of the driving mode on the avalanche statistics is also analyzed.Comment: 28 pages in RevTex, 17 figure

Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease

Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo

A multicenter study on chronic cough in children: Burden and etiologies based on a standardized management pathway

Background: While the burden of chronic cough in children has been documented, etiologic factors across multiple settings and age have not been described. In children with chronic cough, we aimed (1) to evaluate the burden and etiologies using a standar