The long term goal of our research is to elucidate whether DJ-1 and its related pathways represent a convergent mechanism for disorders involving dopaminergic dysfunction. The objectives of this pilot proposal are: (1) to determine whether the Parkinson's disease-associated protein DJ-1 contributes to the molecular mechanisms underlying reward acquisition in the mesolimbic pathway, and (2) whether behaviors in response to psychomotor stimulants are altered in DJ-1-deficient mice. Cellular localization of the dopamine transporter (DAT) regulates dopamine uptake activity and thus represents a target mechanism underlying addiction. Our transgenic mouse model the DJ-1-deficiency demonstrates enhanced presynaptic DAT levels, which leads to increased vulnerability to neurotoxicants in models of Parkinson's disease. No thorough analysis of the impact of DJ-1 and its related mechanisms on dopaminergic neurotransmission in the mesolimbic pathway has been performed. We posit that DJ-1 deficiency likely alters DAT localization and activity in the mesolimbic pathway, and through this mechanism, may contribute to behavioral changes following exposure to drugs of abuse. If our hypotheses are correct, these studies should identify a novel mechanism involved in reward acquisition and provide a new target for therapeutics to counter the addictive effects of drugs of abuse.
Use of cocaine and methamphetamine (METH) contributes to morbidity and mortality in nearly 7 million Americans (2008 National Survey on Drug Use and Health). Currently, few therapeutic options are available to inhibit drug-seeking behaviors. The long-term goal of our research is to delineate novel targets that affect reward responses in the brain. On the path to achieving this goal, we propose to identify new pathological substrates of the mechanisms that contribute to development of addiction, specifically the Parkinson's disease (PD)-related protein DJ-1. Our studies in DJ-1-deficient transgenic mice have revealed alterations in the dopamine transporter (DAT) that contribute to neuronal vulnerability and locomotor impairments in the nigrostriatal pathway. Because DAT is integral to the reward response, we expect that DJ-1 or its related mechanisms may contribute to reward acquisition in models of psychomotor stimulant use.
