Grant: Project Grant

Substance abuse and other addictions have staggering societal and personal costs. Treatments for these conditions are few or ineffective with high incidence of relapse. This project proposes a novel approach, seeking to target a mechanism in brain we discovered that promotes drug seeking behaviour. Drugs of abuse release dopamine in brain to produce pleasurable effects. Dopamine has classically been associated with brain reward, acting through specific dopamine receptors. However, when drugs of abuse are used repeatedly, we discovered a parallel physiological anti-reward mechanism is activated that encodes aversion. The aversive mechanism we identified also functions through dopamine, by activating a subpopulation of neurons expressing 2 types of dopamine receptors to generate a receptor complex with alternative signaling. We propose this mechanism becomes aberrant and upregulated with repeated drug abuse, eventually promoting drug-seeking behavior. The proposed research will study this anti-reward mechanism to eventually target it to reduce drug seeking and craving. In keeping with two-fold higher incidence of addiction in men compared to women, we found higher levels of the aversive receptor complex in female rats compared to males. Further, levels of the complex were significantly lower in adolescent rats compared to adults, suggesting lower activity of the aversion mechanism in adolescents, which may predispose them to experience a higher degree of reward and therefore develop addiction more easily. We will activate/inactivate the neurons that coexpress the receptors and attempt to disrupt the receptor complex in rodent models using pharmacologic and genetic manipulations to establish their definitive role in reducing reward related to drugs of abuse. Identifying the mechanism by which this receptor complex functions may define a potential target for treating disorders such as drug addiction which creates public health issues of enormous magnitude.