5-HT6R-ATR-primary cilia network supports morphine-related memory extinction in the medial prefrontal cortex

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.