Selective Dopamine Transporter Inhibition with CE-123 Promotes Fear Extinction and Alters the Basolateral Amygdala...

Persistent fear responses and impaired fear extinction are characteristic features of stress-related disorders. Dopaminergic signalling within amygdala-centred circuits contributes to fear extinction, but the associated molecular mechanisms remain unclear. Here, we investigated whether selective dopamine transporter (DAT) inhibition with CE-123 (10 mg/kg, intraperitoneally) facilitates fear extinction and induces region-specific molecular adaptations. Adolescent male rats were subjected to a modified stress-enhanced fear learning (SEFL)-like paradigm followed by extinction training. Rats exposed to high-intensity fear conditioning (STRESSED groups) displayed persistent freezing and increased anxiety-like behaviour compared with non-shocked controls (NON-STRESSED groups). Repeated CE-123 administration during extinction significantly reduced freezing in stressed rats without affecting non-stressed animals. Quantitative proteomic analyses of the basolateral amygdala (BLA) and hippocampus (HPC) revealed marked region-specific effects. Stress-related fear enhancement induced extensive proteomic remodelling in the BLA, involving proteins associated with glutamatergic signalling, synaptic plasticity, and axonal organization, whereas the hippocampal proteome was largely unaffected. CE-123 also produced BLA-specific molecular effects, reducing the abundance of proteins associated with mitochondrial ATP synthesis in non-stressed animals and with ribosomal, mitochondrial, and RNA-processing pathways in stressed rats. These findings identify the BLA as a key substrate of fear-related molecular adaptations and demonstrate that selective DAT inhibition modulates amygdala proteomic architecture during fear extinction. Overall, the results support further investigation of DAT modulation as a potential strategy for facilitating fear extinction in stress-related disorders.