Attenuation of Novelty-Induced Hyperactivity of Gria1-/- Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics
Attenuation of Novelty-Induced Hyperactivity of Gria1-/- Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics
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DOI：
10.3389/fphar.2019.00309
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发表时间：
2019-03-29
影响因子：
5.6
通讯作者：
Korpi, Esa R.
中科院分区：
文献类型：
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作者：
Aitta-aho, Teemu;Maksimovic, Milica;Korpi, Esa R.
AMPA受体GluA 1亚基缺陷的基因靶向小鼠（Gria 1-/-小鼠）在新的环境中表现出强大的过度运动，这表明它们构成了多动障碍，如躁狂症，精神分裂症和注意缺陷多动障碍的模型。这种行为改变与海马神经元激活增加有关，并且可以通过抗躁狂药物（如锂、丙戊酸和拉莫三嗪）的长期治疗来减弱。现在，我们发现全身性大麻二酚强烈减弱了Gria 1-/-小鼠的多动症和海马c-Fos表达，而不影响野生型同窝对照。急性双侧背海马内输注大麻二酚部分阻断了Gria 1-/-小鼠的活动过度，但对野生型小鼠没有影响。氯氮平-N-氧化物在背侧海马中激活抑制性DREADD受体hM 4Gi，强烈抑制了Gria 1-/-小鼠的活动过度，但对野生型小鼠的运动没有影响。我们的研究结果表明，海马神经元兴奋性增强与GluA 1亚基缺陷小鼠明显的新奇诱导的活动过度有关。当海马神经元对新刺激的这种增强反应通过药物治疗或化学发生抑制在海马中特异性降低时，Gria 1-/-小鼠从行为过度活跃中恢复，这表明过度活跃行为中的海马功能障碍可以用大麻酚治疗。
Gene-targeted mice with deficient AMPA receptor GluA1 subunits (Gria1-/- mice) show robust hyperlocomotion in a novel environment, suggesting them to constitute a model for hyperactivity disorders such as mania, schizophrenia and attention deficit hyperactivity disorder. This behavioral alteration has been associated with increased neuronal activation in the hippocampus, and it can be attenuated by chronic treatment with antimanic drugs, such as lithium, valproic acid, and lamotrigine. Now we found that systemic cannabidiol strongly blunted the hyperactivity and the hippocampal c-Fos expression of the Gria1-/- mice, while not affecting the wild-type littermate controls. Acute bilateral intra-dorsal hippocampal infusion of cannabidiol partially blocked the hyperactivity of the Gria1-/- mice, but had no effect on wild-types. The activation of the inhibitory DREADD receptor hM4Gi in the dorsal hippocampus by clozapine-N-oxide robustly inhibited the hyperactivity of the Gria1-/- mice, but had no effect on the locomotion of wild-type mice. Our results show that enhanced neuronal excitability in the hippocampus is associated with pronounced novelty-induced hyperactivity of GluA1 subunit-deficient mice. When this enhanced response of hippocampal neurons to novel stimuli is specifically reduced in the hippocampus by pharmacological treatment or by chemogenetic inhibition, Gria1-/- mice recover from behavioral hyperactivity, suggesting a hippocampal dysfunction in hyperactive behaviors that can be treated with cannabidiol.