Project Overview

Major depression is common, highly prevalent, potentially lethal, affecting 10% of individuals with significant increase between 2015-2020, and 2-3-fold higher incidence in women compared to men. No cause for this sex difference is known, nor is it addressed by available treatments. Current antidepressants targeting serotonin/noradrenergic systems are ineffective in many, with long time-lags for efficacy, with newer treatments not having diminished disease burden.
Dopamine classically is associated with brain reward, acting through specific receptors. We discovered a parallel physiological anti-reward mechanism encoding aversion and anhedonia in brain, functioning through dopamine, activating a receptor complex with alternate signaling. We propose this mechanism becomes aberrant and overactive in major depression. The proposed research will analyze and target this aversion mechanism to alleviate depression and anxiety.
We discovered that activating the dopamine receptor complex in rats induced depression- and anxiety-like behavior, but more easily in females. In keeping with higher depression incidence in women, we found higher aversive complex in female rat and monkey brains compared to male. Disrupting the complex by a peptide we devised reversed depressive and anxiety effects. Thus, sex differences in an aversion mechanism contribute to increased predisposition of female rats to develop depressive and anxiety-like behavior.
We will validate our hypothesis in rodents using pharmacologic and genetic manipulations to establish definitive roles of this mechanism to induce depressive and anxiety-like behaviors in both sexes, evaluate its expression in postmortem human brain from depressed individuals compared to matched controls, develop a preclinical positron-emission imaging system to measure the complex in live animals to propel similar development for human brain imaging, and continue to refine strategies to target the function of the complex with the goal of drug discovery. These studies should consolidate evidence identifying this female-specific mechanism as a drug development target for effective treatment of depression and anxiety.

Team Members

Susan George, University of Toronto

Partners and Donors

The Krembil Foundation

Women's Brain Health Initiative