The delta opioid receptor agonist KNT-127 relieves innate anxiety-like behavior in mice by suppressing transmission from the prelimbic cortex to basolateral amygdala.

IF 2 Q3 NEUROSCIENCES
Neuropsychopharmacology Reports Pub Date : 2024-03-01 Epub Date: 2023-12-29 DOI:10.1002/npr2.12406
Ayako Kawaminami, Daisuke Yamada, Toshinori Yoshioka, Azumi Hatakeyama, Moeno Nishida, Keita Kajino, Tsuyoshi Saitoh, Hiroshi Nagase, Akiyoshi Saitoh
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Abstract

Aim: Excitatory projections from the prelimbic cortex (PL) to the basolateral nucleus of the amygdala (BLA) are implicated in the regulation of anxiety-like behaviors, and we previously demonstrated that anxiolytic-like effects of the selective delta-opioid receptor (DOP) agonist KNT-127 is involved in suppressing glutamate neurotransmission in the PL. Here, we investigated the mechanisms underlying the anxiolytic-like effect of KNT-127 in mice by combining optogenetic stimulation of the PL-BLA pathway with behavioral analyses.

Methods: Four-week-old male C57BL/6J mice received bilateral administration of adeno-associated virus (AAV)2-CaMKIIa-hChR2(H134R)-enhanced yellow fluorescent protein (EYFP) into the PL to induce expression of the light-activated excitatory ionic channel ChR2. Subsequently, an optic fiber cannula connected to a wireless photo-stimulator was implanted into the BLA for optogenetic PL-BLA pathway stimulation. We evaluated innate anxiety using the elevated plus maze (EPM) and open field (OF) tests as well as learned anxiety using the contextual fear conditioning (CFC) test.

Results: Optogenetic activation of the PL-BLA pathway enhanced anxiety-like behaviors in the EPM and OF, while prior subcutaneous administration of KNT-127 (10 mg/kg) reduced this anxiogenic effect. In contrast, optogenetic activation of the PL-BLA pathway had no significant effect on conditioned fear.

Conclusion: Our findings indicate that the PL-BLA circuit contributes to innate anxiety and that the anxiolytic-like effects of KNT-127 are mediated at least in part by suppression of PL-BLA transmission. The PL delta-opioid receptor may thus be an effective therapeutic target for anxiety disorders.

δ阿片受体激动剂KNT-127通过抑制从边缘前皮层到杏仁核基底外侧的传导,缓解了小鼠的先天焦虑样行为。
目的:从边缘前皮层(PL)到杏仁核基底外侧核(BLA)的兴奋性投射与焦虑样行为的调节有关,我们以前曾证明选择性δ-阿片受体(DOP)激动剂KNT-127的抗焦虑样效应参与抑制PL的谷氨酸神经递质。在此,我们通过结合光遗传刺激 PL-BLA 通路和行为分析,研究了 KNT-127 在小鼠体内产生抗焦虑样效应的机制:4周大的雄性C57BL/6J小鼠接受了腺相关病毒(AAV)2-CaMKIIa-hChR2(H134R)-增强黄色荧光蛋白(EYFP)的双侧给药,以诱导光激活兴奋性离子通道ChR2的表达。随后,将连接无线光刺激器的光导纤维插管植入BLA,对PL-BLA通路进行光遗传刺激。我们使用高架迷宫(EPM)和开放场(OF)测试评估了先天焦虑,并使用情境恐惧条件反射(CFC)测试评估了后天焦虑:结果:PL-BLA通路的光遗传激活增强了EPM和OF中的焦虑样行为,而事先皮下注射KNT-127(10 mg/kg)则降低了这种致焦效应。相比之下,光遗传激活PL-BLA通路对条件性恐惧没有显著影响:结论:我们的研究结果表明,PL-BLA通路有助于产生先天性焦虑,而KNT-127的抗焦虑样效应至少部分是通过抑制PL-BLA传导介导的。因此,PL δ-阿片受体可能是焦虑症的有效治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neuropsychopharmacology Reports
Neuropsychopharmacology Reports Psychology-Clinical Psychology
CiteScore
3.60
自引率
4.00%
发文量
75
审稿时长
14 weeks
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