Circadian rhythms dominate a large array of physiological, biochemical and behavioral responses and their disruption may lead to depression, insomnia, bipolar disorders and other mental illnesses. Recent evidence demonstrates intimate links between the circadian clock and metabolism. While it is well documented that drugs of abuse disrupt circadian rhythms, it is still unclear how this may happen and how profound is the influence of drugs of abuse on cellular metabolism. The intellectual merit of this application is to decipher and interpret at the molecular level a seriesof fascinating observations showing that dysfunctions of the dopaminergic system, induced by drugs of abuse, are associated with disruption of the circadian rhythms. Dopamine is a key molecule in the process of addiction. Dopamine also regulates motor and hormonal activities, and has a leading role in controlling motivated and emotional behaviors. This application is focused on one principal element of the dopaminergic system, the dopamine D2 receptor (D2R). D2Rs are key players in the control of the cellular and behavioral responses that regulate motor function, brain reward circuitries and endocrine control. Intriguingly, these functions are also modulated in a circadian manner. Results gathered in our laboratories have revealed a molecular link between D2R-mediated signaling and control of the circadian machinery. This application is highly focused to solve a question of broad biological significance: deciphering the causal link between dopamine-mediated signalling, the circadian clock and drugs of abuse. Our innovative mass-spectrometry approach coupled with state-of-the-art biocomputing, will decipher, for the first time, the metabolome map of brain areas involved in clock control and in response to drugs of abuse. The application, in addition of being highly targeted, has much broader impact as it tackles a conceptual question of basic importance. Indeed, the proposed research will generate outcomes that are likely to branch towards exciting new avenues that embrace additional fields of research. It is thereby highly likely that this project constitutes a valuable gateway to the broader field of study related to the role played by metabolic and epigenetic events in neuronal responses, with implications of opening novel avenues for therapeutic intervention in brain disorders. The outcome of the proposed research will develop in future directions including a comparative metabolome analysis of various drugs of abuse in various animal models.
Circadian rhythms dominate a large array of physiological, biochemical and behavioral responses. This application is aimed at deciphering the molecular and metabolic pathways that modulate the clock machinery by dysfunctions of the dopaminergic system induced by drugs of abuse. Specifically, we will focus on the consequences of disruption of the dopamine D2 receptor (D2R)- mediated signalling, a key receptor in the control of motivated behaviors. We will establish the first metabolome map in response to cocaine and along the circadian cycle. This application is relevant to clinical studies since there is reduced availability of D2R and disrupted circadian rhythms in the brain of cocaine addicts.
|Kharkwal, Geetika; Radl, Daniela; Lewis, Robert et al. (2016) Dopamine D2 receptors in striatal output neurons enable the psychomotor effects of cocaine. Proc Natl Acad Sci U S A 113:11609-11614|