J Cereb Blood Flow Metab. 2015 Jul;35(7):1169-74. doi: 10.1038/jcbfm.2015.35. Epub 2015 Mar 25.

Imaging in vivo glutamate fluctuations with [(11)C]ABP688: a GLT-1 challenge with ceftriaxone.

Zimmer ER¹, Parent MJ², Leuzy A², Aliaga A³, Aliaga A⁴, Moquin L⁵, Schirrmacher ES³, Soucy JP³, Skelin I³, Gratton A⁵, Gauthier S⁶, Rosa-Neto P⁷.

Author information

1: 1] Translational Neuroimaging Laboratory (TNL), McGill Center for Studies in Aging, Douglas Mental Health University Institute, Verdun, Quebec, Canada [2] Alzheimer's Disease Research Unit, McGill Centre for Studies in Aging, McGill University, Montreal, Quebec, Canada [3] Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
2: 1] Translational Neuroimaging Laboratory (TNL), McGill Center for Studies in Aging, Douglas Mental Health University Institute, Verdun, Quebec, Canada [2] Alzheimer's Disease Research Unit, McGill Centre for Studies in Aging, McGill University, Montreal, Quebec, Canada.
3: Montreal Neurological Institute (MNI), Montreal, Quebec, Canada.
4: Translational Neuroimaging Laboratory (TNL), McGill Center for Studies in Aging, Douglas Mental Health University Institute, Verdun, Quebec, Canada.
5: Department of Psychiatry, Douglas Hospital Research Centre, McGill University, Montreal, Quebec, Canada.
6: Alzheimer's Disease Research Unit, McGill Centre for Studies in Aging, McGill University, Montreal, Quebec, Canada.
7: 1] Translational Neuroimaging Laboratory (TNL), McGill Center for Studies in Aging, Douglas Mental Health University Institute, Verdun, Quebec, Canada [2] Alzheimer's Disease Research Unit, McGill Centre for Studies in Aging, McGill University, Montreal, Quebec, Canada [3] Montreal Neurological Institute (MNI), Montreal, Quebec, Canada.

Abstract

Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [(11)C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [(11)C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BP(ND)) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [(11)C]ABP688 BP(ND) in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions.