Neuropharmacological and Neurobiological Relevance of In vivo 1H-MRS of GABA and Glutamate for Preclinical Drug Discovery in Mental Disorders

Abstract

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.

Neuroimaging studies of GABA in schizophrenia: a systematic review with meta-analysis

“…Although they found no difference between patients with schizophrenia and controls, when the analysis was restricted to the subgroup of patients that were antipsychotic-naive, the increase in GABA following tiagabine was significantly diminished. Tiagabine-induced increases in cortical GABA are not detectable using 1 H-MRS, 85 , 86 which is consistent with the view that the GABA 1 H-MRS signal principally reflects nonsynaptic GABA. Pharmacologically induced alterations in synaptic GABA may be more sensitively imaged with [ 11 C]Ro15-4513 PET, because it is a GABA A /BZR inverse agonist with greater selectivity for intra-synaptic receptors.…”

Aripiprazole and Riluzole treatment alters behavior and neurometabolites in young ADHD rats: a longitudinal 1H-NMR spectroscopy study at 11.7T

“…In good correlation with the data shown by the in vivo pharmaco-( 1 H)MRS study on adults female Sprague Dawley rats, in our study riluzole heavily reduced glutamate in the PFC and to some extent also glutamine, but not GABA. 45 Together with its function as glutamatergic modultator, riluzole was found to readily reduce also total creatine and inositoles level indicating its role in cell plasticity. Given the higher levels of choline, total NAA and creatine were found within the right prefrontal white matter of OCD patients, correlating with the severity of symptoms, 46 our results support the hypothesis that riluzole is an effective drug for the treatment of OCD symptoms.…”

Effects of γ‐Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and γ‐Aminobutyric acid metabolism in the anesthetized rat In vivo

“…Tiagabine raises the brain extracellular GABA level measured by microdialysis in a dose‐ and region‐dependent manner (Fink‐Jensen et al, ), whereas the tissue GABA level measured by 1 H‐MRS is unaltered in awake humans (Myers et al, ) or slightly increased in anesthetized rodents (∼7–8% increase for 20–40 mg/kg; Waschkies et al, )), and no changes were seen in mice given up to 10 mg/kg following repeated daily dosing for 8 days (Leach et al, ; Sills et al, ). This effect contrasts sharply with the large decrease in tissue concentrations of monoamines seen with administration of reuptake blockers or knockout of plasma membrane transporters (Benoit‐Marand et al, ; Pereira and Sulzer, ), emphasizing the importance of additional clearance and resupply pathways in the case of GABA.…”