IGF-1 Microinjection in the Prefrontal Cortex Attenuates Fentanyl-Seeking Behavior in Mice.
IGF-1 Microinjection in the Prefrontal Cortex Attenuates Fentanyl-Seeking Behavior in Mice.
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DOI：
10.1093/ijnp/pyad013
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发表时间：
2023-05-31
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影响因子：
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阿片类药物使用障碍（OUD）是一种慢性复发性精神疾病，具有巨大的社会经济负担。阿片类药物过量死亡已达到流行病水平，尤其是芬太尼。治疗 OUD 的最大挑战之一是长期戒毒后复发寻求药物。据报道，胰岛素样生长因子-1 (IGF-1) 异常在多种神经和精神疾病中存在，包括 OUD。然而，IGF-1 及其下游信号通路是否与芬太尼复发相关仍不清楚。小鼠每天接受 2 小时芬太尼（10 μg/mL，27 μL/输注）口服自我给药训练，持续 14 天，随后 14 天停止芬太尼。检测背内侧前额叶皮层（dmPFC）中IGF-1/IGF-1受体及其下游信号通路的表达水平。然后，从芬太尼戒断第9天到第13天，将IGF-1双侧显微注射到dmPFC中。评估PFC中锥体神经元的芬太尼寻求行为和兴奋性突触传递。我们发现，芬太尼口服自我给药停止 14 天会导致 dmPFC 中 IGF-1 和 IGF-1 受体磷酸化显着下调。这些变化伴随着下游 Akt 和 S6 信号通路的抑制。此外，在 dmPFC 中局部施用 IGF-1 可减弱环境诱导的芬太尼寻求行为。此外，电生理学和免疫组织化学分析表明，IGF-1阻断芬太尼诱导的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸和N-甲基-D-天冬氨酸受体介导的兴奋性突触传递的还原以及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体和N-甲基-D-天冬氨酸受体亚基的突触表达。这些结果表明，PFC 中的 IGF-1 在长期停止芬太尼口服自我给药后调节芬太尼寻求方面发挥着关键作用。
Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder with an enormous socioeconomic burden. Opioid overdose deaths have reached an epidemic level, especially for fentanyl. One of the biggest challenges to treat OUD is the relapse to drug seeking after prolonged abstinence. Abnormalities in insulin-like growth factor-1 (IGF-1) have been reported in various neurological and psychiatric disorders, including OUD. However, whether IGF-1 and its downstream signaling pathways are associated with relapse to fentanyl seeking remains unclear. Mice were subjected to daily 2-hour fentanyl (10 μg/mL, 27 μL/infusion) oral self-administration training for 14 days, followed by 14-day fentanyl cessation. Expression levels of IGF-1/IGF-1 receptor and downstream signaling pathways in the dorsomedial prefrontal cortex (dmPFC) were detected. Then, IGF-1 was bilaterally microinjected into the dmPFC from fentanyl cessation day 9 to day 13. Fentanyl-seeking behavior and excitatory synaptic transmission of pyramidal neurons in PFC were evaluated. We found that 14-day cessation from fentanyl oral self-administration caused significant downregulation of IGF-1 and IGF-1 receptor phosphorylation in the dmPFC. These changes were accompanied by inhibition of the downstream Akt and S6 signaling pathway. In addition, local administration of IGF-1 in the dmPFC attenuated context-induced fentanyl-seeking behavior. Furthermore, electrophysiology and immunohistochemistry analyses showed that IGF-1 blocked fentanyl-induced reduction of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors-mediated excitatory synaptic transmission as well as synaptic expression of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and N-methyl-D-aspartate receptor subunits. These results suggest that IGF-1 in the PFC plays a pivotal role in regulating fentanyl seeking after prolonged cessation from fentanyl oral self-administration.
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DOI：
10.1523/jneurosci.3216-18.2021
发表时间：
2021-03-17
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
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影响因子：
25
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Shaham, Yavin
影响因子：
11.5
作者：
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Macaulay, Valentine M.
影响因子：
15.1
作者：
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Cisneros, Irma E.
DOI：
10.1523/jneurosci.0005-12.2012
发表时间：
2012-04-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
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作者：
Bossert JM;Stern AL;Theberge FR;Marchant NJ;Wang HL;Morales M;Shaham Y
通讯作者：
Shaham Y