Deep brain stimulation (DBS) targeting the medial forebrain bundle (MFB) is emerging as a promising intervention for treatment-resistant depression. Our study systematically investigated the NA system in a depression model and explored the modulatory effects of mfb-DBS on this system.Using Flinders Sensitive Line (FSL) rats as a depression model and Sprague Dawley (SD) rats as controls, we examined the spatial distribution and myelination of NA fibers within the mfb under confocal microscopy, monitored real-time in vivo NA release in response to mfb-DBS in the mPFC and NAC during 6 different stimulation parameters, while assessed the vocalization behavioral changes. Additionally, we quantified the activation of ascending projecting NA cell groups (A1, A2, A6), parvalbumin-mediated microcircuitry, and total neuronal activation in the mPFC and NAC with or without stimulation.Our findings revealed that NA fibers in the mfb were unmyelinated thin fibers with bulging varicosities and were less abundant in FSL rats. DBS increased NA release in both groups, with a more pronounced effect in depression model’s NAC. We observed an evoked dual peak NA release, suggesting dual mechanisms of activation of these fibers. FSL rats exhibited more positive affective vocalizations following mfb-DBS. Unilateral stimulation bilaterally reactivated A1 and A2 cell groups in the depression model. Finally, DBS appeared to modulate the parvalbumin interneuron-mediated feedforward circuit in the mPFC and NAC of FSL rats.This study delineates the altered NA activity in the FSL depressive model, highlighting the intricate interactions between the noradrenergic system and mfb-DBS in rodent models.