Neuropharmacological and neurobiological relevance of in vivo ¹H-MRS of GABA and glutamate for preclinical drug discovery in mental disorders.
Proton magnetic resonance spectroscopy ((1)H-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 (1)H-MRS shall serve for decision making in preclinical pharmaceutical drug discovery, it has to meet stringent requirements. In particular, (1)H-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 (1)H-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, (1)H-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 mm(3) volumes-of-interest. Taken together, these findings demonstrate the value and limitation of quantitative (1)H-MRS of glutamate and GABA for preclinical pharmaceutical research in mental disorders.
1] pRED, Pharma Research & Early Development, DTA Neuroscience, F. Hoffmann-La Roche, Basel, Switzerland [2] Institute for Biomedical Engineering, ETH and University of Zürich, Zürich, Switzerland.
Conny F
CF
Waschkies
pRED, Pharma Research & Early Development, DTA Neuroscience, F. Hoffmann-La Roche, Basel, Switzerland.
Andreas
A
Bruns
pRED, Pharma Research & Early Development, Discovery Technologies, F. Hoffmann-La Roche, Basel, Switzerland.
Stephan
S
Müller
pRED, Pharma Research & Early Development, DMPK and Bioanalytical R&D, F. Hoffmann-La Roche, Basel, Switzerland.
Martin
M
Kapps
pRED, Pharma Research & Early Development, DTA Neuroscience, F. Hoffmann-La Roche, Basel, Switzerland.
Edilio
E
Borroni
pRED, Pharma Research & Early Development, DTA Neuroscience, F. Hoffmann-La Roche, Basel, Switzerland.
Markus
M
von Kienlin
1] Institute for Biomedical Engineering, ETH and University of Zürich, Zürich, Switzerland [2] Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
Markus
M
Rudin
pRED, Pharma Research & Early Development, DTA Neuroscience, F. Hoffmann-La Roche, Basel, Switzerland.
Basil
B
Künnecke
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy / Q000378:metabolism; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods*; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018683:Excitatory Amino Acid Agents; D018682:GABA Agents; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid