Grant: Project Grant

Depression is highly prevalent, occurring in up to 7% of adults with 3 fold higher incidence in women during their reproductive years and postpartum. No cause for this gender difference is known. Antidepressants are ineffective in many with long time lags for efficacy. We discovered a dopamine D1-D2 receptor complex in brain that when activated in rats induced depression and anxiety like behavior, greater in females who had higher levels of this receptor complex compared to males. Breaking up the D1-D2 heteromer by a peptide we developed reversed the depressive and anxiety effects of the heteromer. We believe sex differences in D1-D2 contribute to the increased predisposition of females to develop depressive behavior. We will evaluate the sex differences in the function of this heteromer and identify the molecular mechanisms by which the D1-D2 complex mediates these effects. We will silence the neurons expressing the D1-D2 heteromer in rats by a designer receptor or by expressing the above peptide or in mice by genetically editing out one of the receptors forming the heteromer to create male and female rat and mouse models that are resilient and resistant to developing depression and anxiety in spite of exposure to chronic unpredictable stress. These studies should consolidate the evidence identifying the D1-D2 heteromer as a target for drug development for effective treatment of depression and anxiety.