Role of 5-HT1A Receptor Stimulation in the Medial Prefrontal Cortex in the Sustained Antidepressant Effects of Ketamine

Background: We previously reported that serotonergic transmission plays an important role in antidepressant effects of ketamine. However, detailed mechanisms have not been elucidated. Among the serotonin receptor subtypes, the serotonin(1A) receptor in the medial prefrontal cortex has an important role in depression. Here, we investigated the role of the medial prefrontal cortex serotonin(1A) receptor and its signaling mechanism in the antidepressant effects of ketamine. Methods: The role of serotonin(1A) receptor-mediated signaling mechanism (phosphoinositide-3 kinase/Akt) in the medial prefrontal cortex was examined in the mouse forced swimming test and western blotting. Results: Ketamine exerted antidepressant effects that lasted for 24 hours, and the sustained antidepressant effects were attenuated by intra-medial prefrontal cortex injection of a serotonin lA receptor antagonist, WAY100635. The sustained antidepressant effects were mimicked by intra-medial prefrontal cortex, but not systemic, administration of a serotonin(1A) receptor agonist, (+/-)-8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT). The sustained antidepressant effects of ketamine and 8-OH-DPAT were abrogated by intra- medial prefrontal cortex injection of a phosphoinositide-3 kinase inhibitor. Ketamine increased the phosphorylation of Akt in the medial prefrontal cortex at 60 minutes after administration, which was blocked by a serotonin(1A) receptor antagonist and a phosphoinositide-3 kinase inhibitor. Furthermore, the sustained antidepressant effects of ketamine and 8-OH-DPAT were attenuated by pretreatment of intra-medial prefrontal cortex injection of a mechanistic target of rapamycin complex-1 inhibitor. Conclusions: These results indicate that selective stimulation of the medial prefrontal cortex serotonin(1A) receptor and subsequent activation of the phosphoinositide-3 kinase/Akt/mechanistic target of rapamycin complex-1 pathway may be necessary for ketamine to exert the sustained antidepressant effects, and that this mechanism could be targeted to develop a novel and effective approach for treating depression.