Even though ketamine has been heralded as a significant advance in the development of novel and rapid treatments for depression, the acute psychotomimetic and reinforcing effects of this drug limit its utility. Previously, we demonstrated that activation of a circuit from the ventral hippocampus to the medial prefrontal cortex is both necessary and sufficient for ketamine?s sustained antidepressant-like effects in rats. In order to test the hypothesis that augmentation of hippocampal activity is capable of producing a sustained antidepressant-like response without also producing abuse-related effects, we evaluated the effects of negative allosteric modulators of alpha-5 GABAA receptors, as these receptors are selectively expressed in the hippocampus. Selective modulation of hippocampal transmission by systemic administration of ?5-GABAA receptor negative allosteric modulator, namely L-655,708, is capable of producing a sustained antidepressant- like effect in the absence of any psychotomimetic or abuse-related effects. In this application, we will utilize conventional pharmacological, electrophysiological, behavioral and chemogenetic approaches to examine the molecular mechanisms by which L-655,708, a negative allosteric modulators the ?5-GABAA receptor, produce sustained antidepressant-like effect. By identifying the mechanisms by which systemic administration of ?5- GABAA receptors negative allosteric modulators recapitulate the therapeutic effects of ketamine without its psychotomimetic and abuse-related effects, it should be possible to provide novel, safe, and effective approaches for treating patients suffering from refractory depression.
Although promising, the use of ketamine to treat refractory depression is limited by adverse effects, including abuse and psychotomimetic effects. We found previously that the hippocampus mediates the beneficial antidepressant-like effects of ketamine, but not the abuse-related effects of ketamine. In this project, we will investigate the mechanisms by which selective pharmacological augmentation of hippocampal activity produces sustained antidepressant-like effects.
