Despite progress in elucidating mechanisms of depression, the efficacy of different treatments remains inadequate. Recent small-scale clinical studies suggested anti-depressant treatment using deep brain stimulation (DBS) of the ventral capsule/ventral striatum or subgenual cingulate cortex (SCC), yet controlled, multi-center trials were unsuccessful. We recently suggested the ventral tegmental area (VTA) as an important intersection for treating depression. We also found that stimulation of the VTA of a genetic rat model of depression (Flinders Sensitive Line (FSL) rats) with a programmed pattern designed to mimic the burst firing of normal rats decreases depressive-like behavior. Herein, we examined the possibility of reaching the VTA - located deep in the brain stem - through its direct connection to the ventro-medial prefrontal cortex (vmPFC), which parallels the human SCC. Thus, we compared treatment of FSLs with modified versions of DBS - either chronic-intermittent low-frequency electrical stimulation of the vmPFC, or patterned acute electrical stimulation (pAES), which integrates transcranial magnetic stimulation properties, namely, bursts of pulse trains and low frequency stimulation, applied to the VTA. We found that stimulation of the vmPFC (20 Hz, 15 min/day, 10 days) improved depressive-like behavior and VTA local field potential (LFP) activity of FSLs, yet it had only a partial long-term effect on behavior. In particular, vmPFC stimulation decreased theta band activity, which correlated with the improvement in depressive-like behavior of all treated FSLs at day 1, and in ˜50% of treated FSLs at day 28 post treatment. pAES of the VTA (10 Hz, 20 min) caused significant, long-term improvement of depressive-like behavior of FSLs, concurrently with normalizing intra-VTA LFP activity, and increasing VTA LFP synchronicity and hippocampal BDNF mRNA levels. Thus, although low-frequency electrical stimulation of the PFC alters VTA activity, leading to attenuation of depressive-like manifestations, a specific stimulation pattern affecting VTA cell programming is important for long-term efficacy.