Examining the neural targets of the AMPA receptor potentiator LY404187 in the rat brain using pharmacological magnetic resonance imaging

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Abstract
Drugs that enhance alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor-mediated glutamatergic transmission, such as the AMPA receptor potentiator LY404187, may form treatment strategies for disorders of cognition, learning and memory. Pharmacological magnetic resonance imaging (phMRI) uses blood oxygenation level dependent (BOLD) contrast as a marker of neuronal activity and allows dynamic non-invasive in vivo imaging of the effects of CNS-active compounds. This study used phMRI to examine the effects of LY404187 in the rat brain. Groups of Sprague Dawley rats (n=7) were anaesthetised and placed in a 4.7 Tesla superconducting magnet before receiving an acute dose of LY404187 (0.5 mg/kg s.c.), either alone or after pretreatment with the selective AMPA/kainate antagonist LY293558 (15 mg/kg s.c.), or LY293558 alone (15 mg/kg s.c.). Brain images were acquired for each subject every minute for 180 min. These volumes were extensively pre-processed before being analysed for changes in BOLD contrast. LY404187 produced significant increases in BOLD contrast in brain regions including the hippocampus, lateral and medial habenulae and superior and inferior colliculi. These changes were blocked by LY293558. When administered alone, LY293558 caused widespread decreases in BOLD contrast. The known actions of LY404187 suggest the observed BOLD signal increases reflect increases in excitatory neurotransmission. The decreases in signal following LY293558 alone are harder to interpret and are discussed in terms of the negative BOLD response. This study provides the first evidence that the effects of AMPA receptor-mediating compounds can be observed using phMRI.