Using pharmacological MRI to map the dose dependent actions of the AMPA potentiator LY451395 in the rat brain

Abstract

Deficits in cognition are common in a range of psychiatric disorders including dementia, schizophrenia and depression. Evidence suggests that enhancement of glutamatergic, and more specifically –amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor-mediated transmission may form a potential treatment strategy for these symptoms (Expert Opin Investig Drugs, 9, 765). Recently, a novel series of biarylsulfonamides, typified by LY451395 and LY404187, that are potent and centrally active AMPA receptor potentiators, have been described (CNS Drug Rev, 8, 255). These compounds act as positive allosteric modulators, increasing ion channel flux in the presence of agonist by suppressing desensitisation and/or deactivation of the receptors and are active in animal models of cognition (Curr Drug Targets CNS Neurol Disord, 3, 181). 2-deoxyglucose autoradiography and c-fos immunocytochemistry techniques show AMPA potentiators act at regions in the rat brain implicated with mnemonic processes such as the hippocampus and the frontal and anterior cingulate cortex (J Cereb Blood Flow Metab, 24, 1098). We have recently reported that the neural targets of a single dose of LY404187 can also be investigated using blood oxygenation level dependant (BOLD) pharmacological magnetic resonance imaging (phMRI [J Psychopharmacol 18 Suppl). The current study aimed to further this work by investigating the effects of a range of doses of the AMPA potentiator LY451395 on BOLD contrast in the rat brain. Male Sprague Dawley rats were anaesthetised with isoflurane, secured in a stereotaxic frame and placed inside a 4.7 Tesla superconducting magnet. Using a continuous, three echo, gradient-echo (GE) sequence (TE = 5, 10, 15 msecs; TR = 940msec; acquisition matrix = 64 64 24; FOV = 4 cm2; yielding an isotropic voxel resolution of 0.5 0.5 0.5 mm), whole brain volumes of 40 slices were acquired every minute for 180 minutes. 30 minutes into the scan subjects received an acute dose of 0.5 mg/kg, 1.5 mg/kg, 3.0 mg/kg LY451395 or vehicle (sc, n=7–9). Brain volumes were realigned, spatially normalised to a randomly chosen template and Gaussian smoothed. Post-processed images were analysed in SPM99 using a fixed-effects General Linear Model multi-subject covariates design. This created statistical parametric maps (SPMs) for each treatment group displaying statistically significant changes in BOLD contrast which correlated with the known pharmacokinetic profile of LY451395. No significant increases in BOLD contrast were observed in the vehicle or 0.5 mg/kg groups. The 1.5 mg/kg group displayed small increases in cortical BOLD contrast. An acute dose of 3.0 mg/kg LY451395 produced widespread bilateral increases in cortical BOLD signal, most notably in the visual and auditory cortices, the temporal association cortex and the ectorhinal cortex as well as a unilateral increase in the thalamus. These results demonstrate that phMRI can detect the dose-dependant actions of LY451395 in the rat brain and add to the accumulating evidence that the technique can be used for non-invasive in vivo investigations into the targets of CNS-active compounds.