Abstract Medication-resistant depression is associated with persistent vocational disability, substantially higher risk of suicide, and higher health care utilization costs. Electroconvulsive therapy (ECT) is an effective course of treatment for medication-resistant depression although it is often poorly tolerated due to memory and cognitive impairment and its mechanism of action remains elusive. Several clinical studies have indicated that repeated, short-term exposure to the volatile anesthetic isoflurane has antidepressant efficacy equivalent to a course of ECT in patients with medication-resistant depression. The antidepressant actions of isoflurane may be due to its ability to elicit cortical burst suppression, a distinctive EEG pattern resembling the postictal EEG following ECT-induced seizures. Recently, we found that that prior exposure to isoflurane in doses that elicit burst suppression reduces the incidence of learned helplessness in rats while comparable doses of halothane, which fail to elicit burst suppression, did not. This R21 application seeks to extend these preliminary findings by testing two overarching hypotheses. First, that cortical burst suppression is necessary and possibly sufficient to explain the antidepressant actions of isoflurane and second that cortical burst suppression and the antidepressant efficacy of isoflurane and related anesthetics are dependent on activation of the ATP-gated K+ channel, a conductance explicitly coupled to cellular energetics and metabolism. In Specific Aim 1, four anesthetic drugs that differ in their propensity to elicit cortical burst suppression will be evaluated for their ability to reverse maladaptive behaviors, including helplessness and anhedonia, in rats that model aspects of psychopathology in major depressive disorder. In Specific Aim 2, we will determine whether selective ATP- gated K+ channel antagonists are capable of blocking cortical burst suppression and whether loss of this activity prevents isoflurane and related drugs from exerting their antidepressant-like effects in animals. These experiments have the potential to have an important and immediate impact by extending the short list of therapeutic agents available to treat medication-resistant depression to include drugs capable of eliciting cortical burst suppression and by identifying a novel target for the development of drugs with the onset, therapeutic efficacy and duration of ECT but without the side effects that currently limit tolerability.