High-Frequency Stimulation of the Ventral Tegmental Area Rescues Respiratory Failure

Introduction: Opioid use disorder constitutes a significant health crisis in the United States, contributing to high rates of opioid overdose-related deaths. A major driver of these fatalities is fentanyl, a potent synthetic opioid with both sedative and analgesic properties. These properties that make fentanyl clinically effective also increase its addictive potential. Early in opioid addiction, abnormal increases in extracellular dopamine in the nucleus accumbens (NAc) reinforce excessive drug-seeking behaviors which can lead to fatal respiratory depression. Given this mechanism, we investigated whether high frequency stimulation (HFS), mimicking human deep brain stimulation (DBS) of the ventral tegmental area (VTA) could block NAc dopamine increase following an acute lethal dose of fentanyl. We hypothesized that VTA DBS would mitigate these dopaminergic responses and prevent fentanyl-induced respiratory failure. Methods: Multiple cyclic square wave voltammetry (M-CSWV), was applied via a carbon fiber microelectrode in the NAc of urethane-anesthetized male Sprague-Dawley rats. Dopamine levels were recorded at baseline and following acute fentanyl (30 µg/kg, i.v.). HFS (130 Hz frequency, 200 µsec pulse width, and 0.2 mA amplitude) was administered to the VTA before and during fentanyl exposure. Results: Acute fentanyl administration resulted in a 178.2% increase in NAc dopamine levels from baseline, accompanied by a decline in respiratory rates to critically low levels (45 breaths per minute vs. 102 bpm), eventually resulting in 100% mortality. HFS of the VTA did not significantly alter baseline tonic dopamine levels or prevent fentanyl-induced dopamine increase in the NAc but was able to fully rescue fentanyl-induced respiratory failure.