Optogenetic Stimulation of <i>Drd1</i> Expressing Neurons Produces Rapid and Long-Lasting Antidepressant Effects

Abstract

Depression and anxiety affect a large portion of society leading to significant social and economic costs. Numerous lines of evidence suggest that impaired function in the prefrontal cortex (PFC) is a key contributor to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by PFC activity. The PFC contains several pyramidal cell subtypes, but it is unclear whether a particular subtype is targeted to produce a rapid antidepressant response. Here we tested two major subtypes, Drd1 and Drd2 dopamine receptor expressing pyramidal neurons and found that targeting and activating channelrhodopsin in Drd1 expressing pyramidal cells produces rapid and long-lasting antidepressant and anxiolytic responses. Importantly, the results demonstrate that optogenetic silencing of Drd1 neurons blocks the rapid antidepressant effects of ketamine. In contrast, photostimulation of Drd2 containing pyramidal cells was ineffective across anxiety and depression measures. Pharmacological approaches also demonstrate that infusion of a D1 receptor agonist into the medial PFC produces antidepressant and anxiolytic responses, while antagonist infusion blocks the effects of ketamine. These findings aid in understanding the cellular target neurons and mechanisms of rapid-acting antidepressants and offer novel therapeutic sites that can impact antidepressant behaviors.