Neuropharmacological and Neurobiological Relevance of In vivo 1H-MRS of GABA and Glutamate for Preclinical Drug Discovery in Mental Disorders
| Autor: | Markus Rudin, Markus von Kienlin, Basil Künnecke, Edilio Borroni, Andreas Bruns, Stephan Müller, Conny Waschkies, Martin Kapps |
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| Přispěvatelé: | University of Zurich, Künnecke, Basil |
| Rok vydání: | 2014 |
| Předmět: |
Pharmacology
Tiagabine Glutamate receptor 10050 Institute of Pharmacology and Toxicology 610 Medicine & health Biology Vigabatrin gamma-Aminobutyric acid Riluzole 170 Ethics 2738 Psychiatry and Mental Health Psychiatry and Mental health Glutamatergic 3004 Pharmacology GABA Agents nervous system medicine 570 Life sciences biology GABAergic 10237 Institute of Biomedical Engineering Neuroscience medicine.drug |
| Zdroj: | Neuropsychopharmacology. 39:2331-2339 |
| ISSN: | 1740-634X 0893-133X |
| Popis: | Proton magnetic resonance spectroscopy (1H-magnetic resonance spectroscopy (MRS)) is a translational modality with great appeal for neuroscience since the two major excitatory and inhibitory neurotransmitters, glutamate, and GABA, can be noninvasively quantified in vivo and have served to explore disease state and effects of drug treatment. Yet, if 1H-MRS shall serve for decision making in preclinical pharmaceutical drug discovery, it has to meet stringent requirements. In particular, 1H-MRS needs to reliably report neurobiologically relevant but rather small changes in neurometabolite levels upon pharmacological interventions and to faithfully appraise target engagement in the associated molecular pathways at pharmacologically relevant doses. Here, we thoroughly addressed these matters with a three-pronged approach. Firstly, we determined the sensitivity and reproducibility of 1H-MRS in rat at 9.4 Tesla for detecting changes in GABA and glutamate levels in the striatum and the prefrontal cortex, respectively. Secondly, we evaluated the neuropharmacological and neurobiological relevance of the MRS readouts by pharmacological interventions with five well-characterized drugs (vigabatrin, 3-mercaptopropionate, tiagabine, methionine sulfoximine, and riluzole), which target key nodes in GABAergic and glutamatergic neurotransmission. Finally, we corroborated the MRS findings with ex vivo biochemical analyses of drug exposure and neurometabolite concentrations. For all five interventions tested, 1H-MRS provided distinct drug dose-effect relationships in GABA and glutamate over preclinically relevant dose ranges and changes as low as 6% in glutamate and 12% in GABA were reliably detected from 16 mm3 volumes-of-interest. Taken together, these findings demonstrate the value and limitation of quantitative 1H-MRS of glutamate and GABA for preclinical pharmaceutical research in mental disorders. |
| Databáze: | OpenAIRE |
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