Abstract：
Previous studies postulated that chronic administration of varenicline, a partial and full agonist at α4β2 and α7 nicotinic acetylcholine receptors (nAChRs), respectively, enhances recognition memory. However, whether its acute administration is effective, on which brain region(s) it acts, and in what signaling it is involved, remain unknown. To address these issues, we conducted a novel object recognition test using male C57BL/6J mice, focusing on the medial prefrontal cortex (mPFC), a brain region associated with nicotine-induced enhancement of recognition memory. Systemic administration of varenicline before the training dose-dependently enhanced recognition memory. Intra-mPFC varenicline infusion also enhanced recognition memory, and this enhancement was blocked by intra-mPFC co-infusion of a selective α7, but not α4β2, nAChR antagonist. Consistent with this, intra-mPFC infusion of a selective α7 nAChR agonist augmented object recognition memory. Furthermore, intra-mPFC co-infusion of U-73122, a phospholipase C (PLC) inhibitor, or 2-aminoethoxydiphenylborane (2-APB), an inositol trisphosphate (IP3) receptor inhibitor, suppressed the varenicline-induced memory enhancement, suggesting that α7 nAChRs may also act as Gq-coupled metabotropic receptors. Additionally, whole-cell recordings from mPFC layer V pyramidal neurons in vitro revealed that varenicline significantly increased the summation of evoked excitatory postsynaptic potentials, and this effect was suppressed by U-73122 or 2-APB. These findings suggest that varenicline might acutely enhance recognition memory via mPFC α7 nAChR stimulation, followed by mPFC neuronal excitation, which is mediated by the activation of PLC and IP3 receptor signaling. Our study provides evidence supporting the potential repositioning of varenicline as a treatment for cognitive impairment.
摘要：
以前的研究假设长期服用伐尼克兰，α4β2和α7烟碱乙酰胆碱受体（nAChRs）的部分和完全激动剂，分别,增强识别记忆。然而,其急性给药是否有效，它作用于哪个大脑区域，以及它所涉及的信号，仍然未知。为了解决这些问题,我们使用雄性C57BL/6J小鼠进行了新的物体识别测试，专注于内侧前额叶皮层（mPFC），与尼古丁诱导的识别记忆增强相关的大脑区域。训练前全身给药伐伦克林剂量依赖性地增强了识别记忆。mPFC内输注varenicline也增强了识别记忆，并且这种增强被选择性α7而不是α4β2nAChR拮抗剂的mPFC内共输注阻断。与此一致，mPFC内输注选择性α7nAChR激动剂增强对象识别记忆。此外，磷脂酶C（PLC）抑制剂U-73122的mPFC内联合输注，或2-氨基乙氧基二苯基硼烷（2-APB），三磷酸肌醇（IP3）受体抑制剂，抑制了伐尼克兰诱导的记忆增强，这表明α7nAChRs也可能充当Gq偶联的促代谢受体。此外,体外mPFCV层锥体神经元的全细胞记录显示，伐尼克兰显着增加了诱发的兴奋性突触后电位的总和，这种效应被U-73122或2-APB抑制。这些发现表明伐尼克兰可能通过mPFCα7nAChR刺激急剧增强识别记忆，其次是mPFC神经元兴奋，这是由PLC和IP3受体信号的激活介导的。我们的研究提供了支持伐尼克兰作为认知障碍治疗的潜在重新定位的证据。
