Bio-Imaging Lab, Department of Biomedical Sciences, University of Antwerp, Campus Drie Eiken, D.UC.109, Universiteitsplein 1, 2610, Wilrijk, Belgium.
Psychopharmacology (Berl). 2013 Jun;227(3):479-91. doi: 10.1007/s00213-013-2966-3. Epub 2013 Jan 25.
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.
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.
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.
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.
有效的 NMDA 拮抗剂成像模型可能在推进精神分裂症药物发现研究方面具有关键作用。我们通过行为观察和多模态 MRI 研究了 NMDA 拮抗剂美金刚的亚慢性治疗的影响。
使用药理学 MRI（phMRI）来绘制美金刚急性和亚慢性治疗后的神经解剖结合部位。使用静息态 fMRI（rs-fMRI）和弥散 MRI 研究亚慢性美金刚治疗前后功能连接（FC）和超微结构组织完整性的变化。还记录了进一步的行为证据。
在急性美金刚剂量下观察到前额皮质中的剂量依赖性 phMRI 激活。亚慢性治疗在海马体、扣带回、前额皮质和后扣带回皮质中显示出显著的影响。通过 rs-fMRI 研究发现，海马体和额皮质结构（前额皮质、扣带回）之间的 FC 减少，表明连接丢失。扩散峰度 MRI 显示分数各向异性和平均弥散率变化减少，表明海马体和扣带回皮质的超微结构变化。有限的行为评估表明，美金刚引起的行为效应与其他 NMDA 拮抗剂相当，如运动过度，并且抗精神病药物可以逆转这些效应。
我们的发现证实了这样的假设，即反复 NMDA 受体阻断与非特异性、非竞争性 NMDA 拮抗剂可能导致功能和超微结构改变，特别是在海马体和扣带回皮质。这些变化可能是行为效应的基础。此外，本研究结果强调了多模态 MRI 成像和急性/亚慢性美金刚模型在寻找精神分裂症新型疾病修饰治疗中的应用和转化潜力。
