NOVEL MECHANISMS CONTRIBUTING TO THE ANTIDEPRESSANT-LIKE RESPONSE OF PHARMACOLOGICAL HIPPOCAMPAL ACTIVATION

Even though ketamine has been heralded as a significant advance in the development of novel and rapidtreatments 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 prefrontalcortex is both necessary and sufficient for ketamine?s sustained antidepressant-like effects in rats. In order totest the hypothesis that augmentation of hippocampal activity is capable of producing a sustainedantidepressant-like response without also producing abuse-related effects, we evaluated the effects ofnegative allosteric modulators of alpha-5 GABAA receptors, as these receptors are selectively expressed inthe hippocampus. Selective modulation of hippocampal transmission by systemic administration of ?5-GABAAreceptor 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 utilizeconventional pharmacological, electrophysiological, behavioral and chemogenetic approaches to examine themolecular mechanisms by which L-655,708, a negative allosteric modulators the ?5-GABAA receptor, producesustained 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 itspsychotomimetic and abuse-related effects, it should be possible to provide novel, safe, and effectiveapproaches for treating patients suffering from refractory depression.