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Contact Information:

University of Colorado Denver
Department of Pharmacology
Mail Stop 8303, RC1-North
12800 East 19th Ave
Aurora CO 80045

Phone: (303) 724-3661
Fax: (303) 724-3663
E-mail: nancy.zahniser@ucdenver.edu
curriculum vitae

Affiliated Programs

 

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Regulation of the dopamine transporter and its role in drug addiction.

The brain neuro­­transmitter dopamine (DA) plays an important role in many physiology processes – including move­ment, motivation, reward and affect – and disease states – including Parkinson’s disease, drug addiction and schizophrenia. DA neurotransmission is largely terminated by the DA transporter (DAT), which pumps DA back up into DA neurons.   Widely abused psycho­motor stimulant drugs like cocaine and amphetamine produce many of their activating and rewarding effects by inhibiting and/or reversing the DAT, thereby elevating levels of extracellular DA in the brain and promoting DA-mediated behaviors.  

 

Scenic Colorado Mountains
©2000. Nancy Zahniser. All Rights Reserved

Recently, it has been appreciated that DATs are dynamically regulated. Since DAT activity is so critical for “sculpt­ing” DA neuro­transmission, it is important to understand how this regulation occurs.  Much of my lab’s efforts are focused in this area. Most often, this rapid regulation appears to be due to altered trafficking and cell surface expression of DAT. Specifically, we are investigating regulation induced by DAT sub­strates (e.g., amphet­amine) and inhibitors (e.g., cocaine), growth factor-activated receptor tyrosine kinases and DA D2 autoreceptors. We use several in vitro biochemical approaches to study the cellular and molecular mechan­­isms involved.  In collaboration with Dr. Alexander Sorkin, Depart­ment of Pharm­a­col­ogy, UCD, we also use state-of-the-art fluorescent microscopic and RNA interference (RNAi) approaches to study the endocytic mechan­isms involved in this rapid regula­tion in expression systems. We are currently extending our studies to the rodent brain, using in vitro synaptosomal and slice prepara­tions and primary neuronal cultures.  We also investigate brain regional differ­ences in DAT regulation by measuring in vivo clearance of locally applied DA with high-speed electro­chemical recording.    

The other focus of my lab is to understand how DAT regulation helps to explain individual differences in responsiveness to cocaine and how these differences may impact cocaine addiction.  We typically observe that outbred male Sprague-Dawley rats injected with a low dose of cocaine exhibit a wide range of open-field behavioral activation.  Furthermore, with repeated administra­tion of this dose, rats that were initially less activated develop "behav­ioral sensiti­zation", i.e. enhanced cocaine-induced locomotor activity, whereas the cocaine-induced activity of rats that were initially more highly activated is unchanged.  Our in vivo electrochemical recording showed that a change in the effective­ness of cocaine inhibition of the DAT helps to explain these behavioral differences. Currently, we are using in vitro biochemical assays to explore how cocaine-induced DAT regulation contributes to these differences.  We are also using in vivo micro­dialysis to measure cocaine-induced changes in extracellular DA levels in discrete brain regions while monitoring the rats’ differential behavioral activation. Behavioral sensitization is thought to contribute to drug craving and relapse during abstinence. To determine if differential DAT regulation also impacts cocaine reward, we are collaborating with Dr. Richard Allen, Department of Psychology, UCD, to study cocaine-induced conditioned place preference and self-administration in rats classified as to their initial cocaine locomotor responsiveness.  In the future we anticipate extending our studies to the involvement of DA signaling pathways and contribu­tions from glutamate signaling, as well as to other psychomotor stimulants.  Our hope is that our work will help us to better understand the biological basis of stimulant drug addiction so that therapeutic preventions and interventions will be more effective. 

 

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