In recent decades, non-pharmacological therapies for depression involving direct or indirect stimulation of brain activity have emerged as potential alternates for drug-resistant patients. Vagal nerve stimulation (VNS) involves direct stimulation of the vagus nerve and first emerged as a treatment in intractable epilepsy, but is recognized as a potentially useful mood elevation treatment. Electroconvulsive therapy (ECT), a direct form of electrical brain stimulation, is the most effective antidepressant therapy known. The monoamine noradrenaline curbs neuronal excitability. We tested the hypothesis that the beneficial effects of brain stimulation therapies are mediated, at least in part, through augmentation of the inhibitory effects of cortical monoaminergic neurotransmission, specifically noradrenaline. Two novel models of brain stimulation in Göttingen minipigs, based on human treatment protocols were established. Using the positron emission tomography (PET) ligand [C]-yohimbine, an alpha2 adrenoreceptor antagonist, we determined the changes in adrenergic neurotransmission associated with VNS and ECT brain stimulation. In anesthetized minipigs, PET scans were first acquired 4–6 weeks after the implant of a VNS stimulator before (OFF condition, baseline), within 30 min after the initiation of stimulation at a current intensity of 1 mA (ON condition, acute), and after 3 months of ramped up stimulation to 2 mA (ON condition, chronic). Similarly, we acquired baseline scans in naïve animals and 24–48 h after the end of a clinical course of ECT (10 ECT sessions in anesthetized animals over a 3 week period). Preliminary data demonstrate decreased volumes of distribution of [C]yohimbine to alpha2 adrenoceptors compared with the baseline scans in both stimulation models. Kinetic analysis using the Logan multilinear graphical analysis method in the first three pigs of the VNS study, resulted in a decrease in volume of distribution in the frontal cortex (7% acute, 22% chronic), temporal cortex (12% acute, 22% chronic) and striatum (15% acute, 29% chronic). Data from the first three pigs in the ECT study show a decrease in volume of distribution in the frontal cortex (29%), temporal cortex (25%) and striatum (31%) in ECT treated pigs, 24–48 h after the final ECT treatment. Taken together with published evidence in rodents, these findings lead to at least two conclusions: 1) acute and chronic stimulation affect the cortico-striatal noradrenaline system and 2) yohimbine may be sensitive to competition by the endogenous ligand, and is a possible surrogate marker of noradrenaline release. Further studies are underway to evaluate these hypotheses. The results suggest a possible general mechanism of action for brain stimulation therapies such as ECT and VNS.