Daumas Stéphanie, Betourne Alexandre, Halley Hélène, Wolfer David P, Lipp Hans-Peter, Lassalle Jean-Michel, Francés Bernard
Centre de Recherches sur la Cognition Animale, CNRS UMR 5169, Université Paul Sabatier, Bâtiment 4R3 UFR SVT, Toulouse cedex, France.
Neurobiol Learn Mem. 2007 Jul;88(1):94-103. doi: 10.1016/j.nlm.2007.02.001. Epub 2007 Mar 19.
The hippocampus plays a central role in various forms of complex learning and memory. Opioid peptides and receptors are abundant in the hippocampus. These peptides are co-released with glutamate from mossy fiber- and lateral perforant path-synapses. In this study, we evaluated the functional relevance of the CA3 Kappa opioid receptors (KOR) by transient pharmacological activation or inactivation using single bilateral intrahippocampal microinjections of a selective agonist (U50,488H, 1 or 2.5 nmol), a selective antagonist (nor-binaltorphimine, norBNI 5 nmol) or a mixture of both. C57Bl/6J mice were tested in a fear conditioning paradigm (FC) or in a modified version of the water maze task thought to reveal how flexibly animals can learn and manipulate spatial information (WM). In FC, the agonist (2.5 nmol) decreased context-induced (but not tone-induced) freezing whereas norBNI had no effect. The impairment caused by the agonist U50,488H was blocked by the injection of norBNI, suggesting that overstimulation of CA3-KOR impairs the acquisition and consolidation of contextual fear-related memory. In the WM task, mice were trained repeatedly each day to find a hidden platform. After having reached this goal, the platform position was changed the next day for a new task. U50,488H injection before the last task abolished the previously acquired ability to find rapidly a new platform location, whereas adding norBNI reversed this impairment. Thus, in the mouse, even partial and topographically restricted activation of CA3-KOR entails impairments in two different hippocampus-dependent tasks, indicating functional relevance of the kappa opioid system.
海马体在各种形式的复杂学习和记忆中起着核心作用。阿片肽和受体在海马体中大量存在。这些肽与谷氨酸从苔藓纤维和外侧穿通通路突触共同释放。在本研究中,我们通过单次双侧海马内微量注射选择性激动剂(U50,488H,1或2.5 nmol)、选择性拮抗剂(去甲二氢吗啡酮,norBNI 5 nmol)或两者的混合物,对CA3 κ-阿片受体(KOR)进行短暂的药理学激活或失活,以评估其功能相关性。C57Bl/6J小鼠在恐惧条件反射范式(FC)或改良版水迷宫任务中接受测试,该任务旨在揭示动物学习和操纵空间信息的灵活性(WM)。在FC中,激动剂(2.5 nmol)减少了情境诱导的(而非音调诱导的)僵立反应,而norBNI没有效果。注射norBNI可阻断激动剂U50,488H造成的损伤,这表明CA3-KOR的过度刺激会损害情境恐惧相关记忆的获取和巩固。在WM任务中,小鼠每天反复训练以找到隐藏平台。达到这一目标后,第二天改变平台位置以进行新任务。在最后一项任务前注射U50,488H消除了先前获得的快速找到新平台位置的能力,而添加norBNI可逆转这种损伤。因此,在小鼠中,即使是CA3-KOR的部分和局部受限激活也会导致两种不同的海马体依赖性任务受损,表明κ-阿片系统具有功能相关性。