446. ANTIDEPRESSANT ACTIVITY OF STRATEGIC ELECTRICAL STIMULATION OF PREFRONTOCORTICAL NEURONS PRIMED FOR EXCITABILITY

Abstract Background Major depressive disorder is a severe and pervasive mental health condition that significantly disrupts the well-being and daily functioning of those affected. Despite the availability of various treatment options, their efficacy is often hampered by limited response rates and the presence of adverse side effects, leaving a considerable need for alternative approaches. Advances in neurostimulation technology have emerged as a potential breakthrough in depression treatment, but further research is required to fine-tune these methods and uncover the biological mechanisms underlying their effects. Aims & Objectives This study explores the potential of a novel therapeutic strategy that combines transcranial direct current stimulation (tDCS) with a chemical approach to enhance neuronal excitability (EC stimulation). Method The proposed therapeutic strategy employs NS8593, an antagonist of small-conductance, calcium-activated potassium channels, to prime neurons for excitability. Initial experiments determined subthreshold doses for both tDCS (0.05mA) and NS8593 (1.0mg/kg) individually, neither of which produced measurable behavioral or neurochemical effects in rats. These subthreshold interventions were then combined into a single treatment, referred to as EC stimulation, and assessed in a series of behavioral experiments using the olfactory bulbectomy (OBX) rat model of depression. Results The results demonstrated that EC stimulation effectively reversed hyperactivity induced by OBX in the open field test and reduced anxiety-like behaviors observed in the open field and novelty-suppressed feeding tests, which were otherwise seen with tDCS alone. These behavioral improvements correlated with increased serotonin (5-HT) turnover in the left prefrontal cortex and hippocampus, as evidenced by lower total 5-HT levels and higher levels of its metabolite, 5-HIAA. Furthermore, the combination therapy prevented the rise in hippocampal dopamine levels observed with either tDCS or NS8593 when administered separately. Discussion & Conclusions With depression rates continuing to rise globally, there is an urgent need for innovative treatment strategies that are both effective and safe. The findings of this research highlight the promise of EC stimulation as a potential therapeutic option and underscore the importance of further preclinical studies to advance its development.