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Area:
Dopamine Transporter and Receptors
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High-probability grants
According to our matching algorithm, Kevin Erreger is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2005 — 2008 |
Erreger, Kevin |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Amphetamine Regulation of the Norepinephrine Transporter
DESCRIPTION (provided by applicant): Plasma membrane transporters control the active reuptake of neurotransmitters that mediate chemical signaling in the nervous system. Biogenic amine neurotransmitters (i.e. norepinephrine, NE) play a role in a number of physiological functions including autonomic regulation, locomotion, and complex behaviors such as attention and reward. By terminating these chemical signals, monoamine transporters are critical to the efficient function of the nervous system. The NE system has been implicated in a range of mood and anxiety disorders and the development of drugs such as reboxetine specifically targeting the norepinephrine transporter (NET) are promising therapeutic agents. NET is also a target for drugs of abuse such as the psychostimulants cocaine and amphetamine (AMPH). At present there are few reports of high-resolution measures of intrinsic transporter function. We propose to use NET currents as one measure of transporter activity, including real-time recordings of unitary transporter currents in excised patches. Transporter currents and substrate flux will be used as functional readouts for transporter regulation by AMPH and a range of other modulators. This work will characterize AMPH regulation of monoamine transporter intrinsic function and regulation, and will also be important in building a framework in which to interpret changes caused by physiological modulators, drugs of abuse, and therapeutic agents.
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1 |
2009 — 2010 |
Erreger, Kevin |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. |
D2 Receptor and Food Restriction Regulation of Dopamine Release by Amphetamine
DESCRIPTION (provided by applicant): The dopamine transporter (DAT) is the plasmalemmal membrane protein that mediates the inactivation of released dopamine (DA) through its reuptake. DAT is the major molecular target responsible for the rewarding properties and abuse potential of amphetamine (AMPH), cocaine, arid related psychostimulants. AMPH, as a result of its ability to reverse the inward transport of DA causes DA efflux and therefore increases extracellular DA levels leading to the behavioral effects of AMPH. Recently, the molecular signals controlling AMPH-induced DA release have begun to be elucidated. Importantly, our group has shown that Ca2+/calmodulin dependent protein kinase II (CaMKII) is activated by AMPH and phosphorylates the DAT N-temninus leading to DAT mediated reverse transport of DA. We have recently developed the first detailed kinetic model describing the discrete steps in the functional cycle of the human dopamine transporter (hDAT;Erreger et al., J Neurosci 2008). Therefore, in Aim I we will use this model as a framework to evaluate which specific step(s) of the DAT cycle are affected by CaMKII and DAT N-terminal phosphorylation in order to support AMPH-induced DA efflux. Using animal model and pharmacological approaches it has been shown that D2 DA receptors (D2R) regulate the rewarding effects of AMPH. Importantly, our preliminary data and previous reports also show that D2R stimulation activates CaMKII. Therefore, in Aim II we will test the hypothesis in DA neurons that D2R signaling regulates AMPH-induced DA release in a CaMKII dependent manner. Changes in nutritional status (e.g. food-restriction, FR) regulate sensitivity to the rewarding and locomotor effects of AMPH. Notably, FR increases both D2R density and CaMKII activation. Therefore, in Aim III we will use acute striatal slices to determine how D2R signaling regulates AMPH-induced DA release in FR and control animals. In this Aim, we will clarify whether FR affects the ability of AMPH to cause DA efflux by altering D2R signaling. This proposal will allow the candidate to develop all of the skills and training to establish in his own lab and independent research program uncovering new cellular/pharmacological targets to regulate the actions of AMPH. PUBLIC HEALTH RELEVANCE: Abuse of psychostimulants such as amphetamine, methamphetamine, and cocaine represents a major public health problem. Treatment has been hampered by a lack of a complete understanding of how amphetamine works. By defining novel signaling pathways affected by amphetamine we will uncover new potential therapeutic targets for psychostimulant abuse.
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1 |