5-HT6R-ATR-Primary Cilia Network Supports Memory Extinction

Drug addiction represents a pathological form of learning and memory with profound implications for individuals and society. The serotonin receptor 5-HT6R, uniquely expressed on primary cilia, is associated with neurological development, cognitive impairments, emotional disorders, and reward memory for cocaine and nicotine. However, its role in morphine-related reward memory remains unclear. This study demonstrated that 5-HT6R expression was downregulated during the early stage of morphine-induced conditioned place preference (CPP) extinction but returned to baseline levels later, with no significant changes observed during CPP establishment or reinstatement. Knocking down 5-HT6R accelerated CPP extinction, while overexpression prolonged the process. Furthermore, primary cilia defects within the mPFC were noted during the early stage of CPP extinction, and the removal of primary cilia expedited this process. Finally, ATR was identified as a novel target molecule of 5-HT6R, and the 5-HT6R-ATR-primary cilia network was found to regulate morphine-induced CPP extinction, offering new insights for opioid addiction therapy.