Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI.
BACKGROUND
An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI.


METHODS
Pharmacological MRI (phMRI) was used to map the neuroanatomical binding sites of memantine after acute and subchronic treatment. Resting state fMRI (rs-fMRI) and diffusion MRI were used to study the changes in functional connectivity (FC) and ultra-structural tissue integrity before and after subchronic memantine treatment. Further corroborating behavioural evidences were documented.


RESULTS
Dose-dependent phMRI activation was observed in the prelimbic cortex following acute doses of memantine. Subchronic treatment revealed significant effects in the hippocampus, cingulate, prelimbic and retrosplenial cortices. Decreases in FC amongst the hippocampal and frontal cortical structures (prelimbic, cingulate) were apparent through rs-fMRI investigation, indicating a loss of connectivity. Diffusion kurtosis MRI showed decreases in fractional anisotropy and mean diffusivity changes, suggesting ultra-structural changes in the hippocampus and cingulate cortex. Limited behavioural assessment suggested that memantine induced behavioural effects comparable to other NMDA antagonists as measured by locomotor hyperactivity and that the effects could be reversed by antipsychotic drugs.


CONCLUSIONS
Our findings substantiate the hypothesis that repeated NMDA receptor blockade with nonspecific, noncompetitive NMDA antagonists may lead to functional and ultra-structural alterations, particularly in the hippocampus and cingulate cortex. These changes may underlie the behavioural effects. Furthermore, the present findings underscore the utility and the translational potential of multimodal MR imaging and acute/subchronic memantine model in the search for novel disease-modifying treatments for schizophrenia.
Bio-Imaging Lab, Department of Biomedical Sciences, University of Antwerp, Campus Drie Eiken, D.UC.109, Universiteitsplein 1, 2610, Wilrijk, Belgium. sekar.sakthivel@ua.ac.be
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Sekar
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Jonckers
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Verhoye
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Willems
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Veraart
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Van Audekerke
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Couto
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Giugliano
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Wuyts
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Dedeurwaerdere
J
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Sijbers
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Mackie
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Ver Donck
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Steckler
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Van der Linden
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001931:Brain Mapping; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D064847:Multimodal Imaging / Q000379:methods*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D008559:Memantine