Ketamine and Ceftriaxone-Induced Alterations in Glutamate Levels Do Not Impact the Specific Binding of Metabotropic Glutamate Receptor Subtype 5 Radioligand [18F]PSS232 in the Rat Brain.

Adrienne Müller Herde,Silvan Boss,Roger Schibli,Yingfang He,Simon Ametamey,Linjing Mu

doi:10.3390/ph11030083

Adrienne Müller Herde, Silvan Boss + Show 4 more

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https://doi.org/10.3390/ph11030083

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Journal: Pharmaceuticals	Publication Date: Aug 29, 2018
Citations: 4	License type: CC BY 4.0

Affiliation: ETH Zurich, University Hospital of Zurich

Abstract

Several studies showed that [11C]ABP688 binding is altered following drug-induced perturbation of glutamate levels in brains of humans, non-human primates and rats. We evaluated whether the fluorinated derivative [18F]PSS232 can be used to assess metabotropic glutamate receptor 5 (mGluR5) availability in rats after pharmacological challenge with ketamine, known to increase glutamate, or ceftriaxone, known to decrease glutamate. In vitro autoradiography was performed on rat brain slices with [18F]PSS232 to prove direct competition of the drugs for mGluR5. One group of rats were challenged with a bolus injection of either vehicle, racemic ketamine, S-ketamine or ceftriaxone followed by positron emission tomography PET imaging with [18F]PSS232. The other group received an infusion of the drugs during the PET scan. Distribution volume ratios (DVRs) were calculated using a reference tissue model. In vitro autoradiography showed no direct competition of the drugs with [18F]PSS232 for the allosteric binding site of mGluR5. DVRs of [18F]PSS232 binding in vivo did not change in any brain region neither after bolus injection nor after infusion. We conclude that [18F]PSS232 has utility for measuring mGluR5 density or occupancy of the allosteric site in vivo, but it cannot be used to measure in vivo fluctuations of glutamate levels in the rat brain.

Highlights

Glutamate is the principle excitatory neurotransmitter in the nervous system, which elicits its action on ionotropic (N-methyl-D-aspartate receptor (NMDA), Kainate, α-amino-3-hydroxy -5-methyl-4-isoxazolepropionic acid receptor (AMPA)) and metabotropic receptors, especially in the mammalian brain [1]
After co-incubation of rat brain slices with L-glutamate, we found no competition between L-glutamate and [18F]PSS232 binding to metabotropic glutamate receptor 5 (mGluR5)
The binding of [18F]PSS232 was abolished upon co-incubation with the two mGluR5 antagonists, MMPEP and ABP688

Summary

Introduction

Glutamate is the principle excitatory neurotransmitter in the nervous system, which elicits its action on ionotropic (N-methyl-D-aspartate receptor (NMDA), Kainate, α-amino-3-hydroxy -5-methyl-4-isoxazolepropionic acid receptor (AMPA)) and metabotropic (mGluR) receptors, especially in the mammalian brain [1]. In a pharmacological challenge study by Wyckhuys et al [16], N-acetylcysteine (NAc), a compound which facilitates the activity of the cysteine–glutamate antiporter and indirectly increases extrasynaptic glutamate levels [17] did not affect the in vivo binding of [11C]ABP688 in the rat brain. In another pharmacological challenge study, Zimmer et al [15] used the drug ceftriaxone, a potent GLT-1 activator [18], which induces a decrease in extracellular glutamate levels. No information was provided on any other rat brain compartment besides the thalamic ventral anterior nucleus

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