Opioid addiction is driven by maladaptive reward memory, yet its molecular underpinnings remain poorly understood. Circular RNAs (circRNAs) have emerged as key regulators of neuroplasticity, but their roles in addiction-related memory remain unclear. Here, we identify circUnc79, a neuron-enriched and synaptically localized circRNA, as a critical modulator of morphine reward memory in the medial prefrontal cortex (mPFC). In the morphine-induced conditioned place preference (CPP) model, circUnc79 expression is dynamically downregulated during cue-induced memory retrieval. Gain- and loss-of-function experiments demonstrate that circUnc79 bidirectionally regulates the acquisition and persistence of morphine reward memory, without affecting locomotion, anxiety-like behavior, social interaction, or sucrose reward. Mechanistically, circUnc79 acts as a competing endogenous RNA for miR-149-3p, thereby relieving its repression of excitatory amino acid transporter 2 (EAAT2, encoded by Slc1a2). Elevated neuronal EAAT2 enhances presynaptic glutamate reuptake and recycling, supporting reward memory encoding. Manipulation of miR-149-3p produces opposite behavioral and synaptic effects, supporting the functional relevance of this regulatory axis. These findings reveal a circUnc79/miR-149-3p/EAAT2 pathway that regulates synaptic plasticity underlying opioid reward memory and highlight circUnc79 as a potential therapeutic target for opioid use disorders.

Circular RNAs  /  Morphine  /  Opioid addiction  /  Reward memory  /  Synaptic plasticity  /  Medial prefrontal cortex  /  EAAT2  /  miR-149-3p