5-HT6R-ATR-primary cilia network supports morphine-related memory extinction in the medial prefrontal cortex
Summary: Drug addiction involves pathological learning and memory with serious personal and societal effects. Primary cilia on the cell surface are crucial for signal transduction. The 5-HT6R, highly localized in primary cilia, is linked to cognitive and emotional disorders, but its role in morphine...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-09-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225014695 |
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| Summary: | Summary: Drug addiction involves pathological learning and memory with serious personal and societal effects. Primary cilia on the cell surface are crucial for signal transduction. The 5-HT6R, highly localized in primary cilia, is linked to cognitive and emotional disorders, but its role in morphine-related reward memory is unclear. Using a morphine-induced conditioned place preference (CPP) model, we found that 5-HT6R in the medial prefrontal cortex was selectively downregulated during early extinction, but unchanged in CPP establishment or reinstatement. Knockdown of 5-HT6R accelerated extinction, while overexpression delayed it. These effects required intact cilia, as cilia shortening or IFT88 knockdown promoted extinction. Mechanistically, ATR was identified as a 5-HT6R-binding protein that regulates cilia structure. ATR knockdown mimicked and enhanced the extinction-promoting effect of 5-HT6R suppression, which was blocked by cilia disruption. These findings reveal a 5-HT6R–ATR–Primary cilia network that controls the extinction of morphine-induced reward memory, suggesting therapeutic targets for opioid addiction. |
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| ISSN: | 2589-0042 |