Examining the neural targets of the AMPA receptor potentiator LY404187 in the rat brain using pharmacological magnetic resonance imaging
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Drugs that enhance α-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.
KeywordsLY404187 LY293558 AMPA Memory Cognition Glutamate MRI Rat
This research was funded by Eli Lilly and Co. Ltd. The MRI spectrometer was provided by the University of London Intercollegiate Research Service scheme and is located at Queen Mary College London managed by Dr. Alasdair Preston.
- Bleakman D, Schoepp DD, Ballyk B, Bufton H, Sharpe EF, Thomas K, Ornstein PL, Kamboj RK (1996) Pharmacological discrimination of GluR5 and GluR6 kainate receptor subtypes by (3S,4AR,6R,8AR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3 carboxylic acid. Mol Pharmacol 49:581–585PubMedGoogle Scholar
- Brett M, Anton J-L, Valabreque R, Poline J-P (2002) Region of interest analysis using an SPM toolbox. Abstract presented at the 8th International Conference on Functional Mapping of the Human Brain, 2–6 June 2002, Sendai, Japan. Available on CD-ROM in NeuroImage, vol 16, no 2Google Scholar
- Cash D, Read SJ, Lythgoe D, Williams SCR, Roberts TJ, Ireland MD, Smart SC, Hunter AJ (2003) Autoradiographic and functional MRI assessment of rat brain response to amphetamine under halothane and a-chloralose anaesthesia. J Cereb Blood Flow Metab 23:S10Google Scholar
- Chen YC, Galpern WR, Brownell AL, Matthews RT, Bogdanov M, Isacson O, Keltner JR, Beal MF, Rosen BR, Jenkins BG (1997) Detection of dopaminergic neurotransmitter activity using pharmacologic MRI: correlation with PET, microdialysis, and behavioral data. Magn Reson Med 38:389–398PubMedCrossRefGoogle Scholar
- Fowler JH, Whalley K, Murray TK, Ward MA, Crile R, McKinzie D, O’Neill MJ, McCulloch J (2003) Mapping the anatomical substrates of the cognitive enhancing effects of AMPA receptor potentiators with 14C-2-deoxyglucose autoradiography and c-fos immunocytochemistry. J Cereb Blood Flow Metab 23:S10Google Scholar
- Friston KJ, Frith CD, Liddle PF, Dolan RJ, Lammertsma AA, Frackowick AA (1990) The relationship between global and local changes in PET scans. J Cereb Blood Flow Metab 13:1038–1040Google Scholar
- Lowe AS, Barker GJ, Ireland MD, Beech JS, Williams SCR (2005) Estimating global effects from extra-cerebral tissue: inferential utility for pharmacological fMRI. Magn Reson Med, (in press)Google Scholar
- Miu P, Jarvie KR, Radhakrishnan V, Gates MR, Ogden A, Ornstein PL, Zarrinmayeh H, Ho K, Peters D, Grabell J, Gupta A, Zimmerman DM, Bleakman D (2001) Novel AMPA receptor potentiators LY392098 and LY404187: effects on recombinant human AMPA receptors in vitro. Neuropharmacology 40:976–983CrossRefPubMedGoogle Scholar
- O’Neill MJ, Lees KR (2002) Chapter 13, stroke. In: Danysz W, Lodge D, Parsons CG (eds) Ionotropic glutamate receptors as therapeutic targets. FP Graham, Johnson City, pp 403–447Google Scholar
- Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
- Roberts TJ (2004) Structural and functional imaging in an experimental model of Huntington’s disease—mapping pathogenesis and potential therapy. Ph.D. thesis, University of LondonGoogle Scholar
- Schoepp DD, Lodge D, Bleakman D, Leander JD, Tizzano JP, Wright RA, Palmer AJ, Salhoff CR, Ornstein PL (1995) In vitro and in vivo antagonism of AMPA receptor activation by (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5yl)ethyl]decahydroisoquinoline-3-carboxylic acid. Neuropharmacology 34:1159–1168CrossRefPubMedGoogle Scholar
- Smolders I, Bortolotto ZA, Clarke VRJ, Warre R, Khan GM, O’Neill MJ, Ornstein PL, Bleakman D, Ogden A, Weiss B, Stables JP, Ho KH, Ebinger G, Collingridge GL, Lodge D, Michotte Y (2002) Antagonists of GLU(K5)-containing kainate receptors prevent pilocarpine-induced limbic seizures. Nat Neurosci 5:796–804PubMedGoogle Scholar