Opioid dependence (OD) involves maladaptive neuroplasticity in brain reward circuits, particularly within the medial prefrontal cortex (mPFC). While RhoA and NMDA receptors (NMDARs) are implicated in addiction-related synaptic plasticity, their specific interaction within mPFC subregions remains unclear. Using male Sprague-Dawley rats (6 weeks old), we investigated the role of RhoA signaling in the prelimbic cortex (PLC) via behavioral, molecular biological, and electrophysiological assays. Intra-PLC infusion of the RhoA inhibitor Rhosin significantly attenuated morphine-induced conditioned place preference and locomotor sensitization. Furthermore, repeated morphine administration (RMA) upregulated RhoA expression in layer 5 pyramidal neurons. In vitro whole-cell patch-clamp recordings of layer 5 neurons, stimulated at layer 2/3, revealed that Rhosin reduced the amplitude of synaptic NMDAR-mediated excitatory postsynaptic currents. Additionally, using an activity-dependent MK-801 block to isolate extrasynaptic components, we demonstrated that RhoA inhibition significantly attenuated extrasynaptic NMDAR activation, likely by limiting glutamate spillover during high-frequency stimulation. These findings elucidate a critical mechanism by which RhoA mediates opioid-induced neuroadaptations through the regulation of both synaptic and extrasynaptic NMDAR activity, identifying RhoA in the PLC as a promising therapeutic target for opioid dependence.
Dong et al. (Wed,) studied this question.