Knockdown and overexpression of basolateral amygdala SIRT1 via AAV bidirectionally alter morphine-induced conditioned place preference extinction in mice.

INTRODUCTION: This study investigates the role of SIRT1 in basolateral amygdala (BLA) glutamatergic neurons in morphine-induced conditioned place preference (CPP). METHODS: Via SIRT1 knockdown/overexpression in bilateral BLA of morphine-induced CPP mice. Outcomes measured by behavioral tests, WB, and transmission electron microscopy. RESULTS: We found that SIRT1 knockdown prolonged CPP extinction and enhanced reinstatement, whereas overexpression accelerated extinction and attenuated relapse. Behavioral tests revealed that SIRT1 knockdown rescued morphine-induced memory impairment and anxiety-like behaviors, while overexpression exacerbated these effects. Ultrastructural and molecular analyses demonstrated SIRT1 modulation of synaptic plasticity-related proteins (BDNF, PSD95) and synaptic ultrastructure in BLA. DISCUSSION: Our findings reveal that SIRT1 bidirectionally regulates opioid-associated memory persistence through synaptic remodeling, highlighting its potential as an epigenetic target for addiction treatment. While SIRT1 is implicated in neuroplasticity, its specific role in modulating opioid-associated memory circuits within the BLA remains undefined, representing a critical gap in understanding addiction neuropathology.