David Weinshenker, Ph.D.


Office: 367

Lab: 365

Phone: 404-727-3106

Email: dweinshenker@genetics.emory.edu

Additional Contact Information

Mailing Address:

Whitehead Biomedical Research Building

615 Michael St.

Atlanta, GA 30322

Additional Websites

Research Interests

My approach is to use model systems to better understand genes involved in human disease. My lab uses a combination of genetics, pharmacology, behavior, neurochemistry, biochemistry, and electron microscopy to study various aspects of neurobiology and disease including drug addiction, neurodegenerative disease, epilepsy, and affective disorders.

Norepinephrine (NE) is one of the most abundant neurotransmitters in the central and peripheral nervous systems, and has been implicated in many aspects of physiology and behavior. I have taken both genetic and pharmacological approaches to studying NE. Our main genetic model is dopamine beta-hydroxylase knockout (Dbh -/-) mice. Dbh functions in the NE biosynthetic pathway and is required to converts dopamine to NE; thus, Dbh -/- mice completely lack NE and provide a good model to study NE function. The NE system is also amenable to pharmacological manipulation. We employ drugs that activate or inhibit NE receptors, transporters, and biosynthetic enzymes to manipulate the NE system in mice and rats. NE was the originally characterized in the peripheral nervous system and was one of the first neurotransmitter discovered. It has profound effects on almost all aspects of the sympathetic nervous system, including regulation of cardiovascular function and energy metabolism. NE is also abundant in the central nervous system. Most noradrenergic neurons originate in the brainstem in a region called the locus coeruleus (LC). These neurons project to almost every region of the brain; in fact, it is nearly impossible to find a brain structure that completely lacks noradrenergic input. Because it was the first neurotransmitter discovered and is so widespread, NE has been extensively studied for over 30 years by various means. There are three major types of NE receptor (1, 2, and ), all of which are seven-pass transmembrane, G protein-coupled receptors. Stimulation of 1 and  adrenergic receptors increase intracellular Ca++ and cAMP respectively, and are localized on target cells of noradrenergic neurons. Activation of 2 receptors decreases cAMP, and these receptors function as inhibitory autoreceptors and are also found on target neurons. There are 3 subtypes within each of these receptor classes, bringing the total number of identified adrenergic receptors to 9. Selective agonists and antagonists exist for most of these receptors and have been extensively characterized. There are also neurotoxins that are specific for noradrenergic neurons that have been used for many years to study the consequences of destroying NE-containing neurons. Knockout technology has resulted in the generation of mice lacking two different NE biosynthetic enzymes (Dbh and tyrosine hydroxylase) as well as almost every receptor subtype. What makes this system so enticing is that because of the rich history of NE experimentation, there is an abundance of pharmacological tools available for its study.

Drug Addiction

The mesocorticolimbic dopamine (DA) system has been primarily implicated in the reinforcing effects of drugs of abuse.  While this pathway and DA signaling are the focus of most research in this area, it is also clear that norepinephrine (NE), via interactions with the dopaminergic system, plays an important role in modulating the neurochemical and behavioral responses to drugs of abuse in animal models.  This has become of particular interest for two reasons.  First, a common polymorphism in the human Dbh gene is a critical determinant of DBH enzymatic activity and appears to influence behavioral and cognitive responses to cocaine.  Second, the DBH inhibitor disulfiram (Antabuse) has shown striking promise as a treatment for cocaine dependence. We have found that Dbh -/- mice have alterations in DA signaling and are hypersensitive to psychostimulants.  The goal of this research is to further understand how NE influences behavioral and cellular responses to psychostimulants and to explore the possibility that DBH inhibition might be an effective pharmacotherapy for cocaine addiction. We have recently adopted the rat operant self-administration technique to assess the effects of disulfiram and selective DBH inhibitors on cocaine intake and relapse. We are also assessing the subcellular localization of adrenergic receptors within the mesocorticolimbic DA system to gain a more detailed understanding of how NE modulates DA transmission at baseline and following drug exposure. A new project in the lab revolves around how NE-galanin interactions might underlie the ability of voluntary exercise to attenuate cocaine-seeking behavior. We are also interested in assessing the contribution of NE to the effects of other stimulant-like such as amphetamine and the wake-promoting agent and anti-narcoleptic drug modafinil.

Neurodegenerative Disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are neurodegenerative disorders that are characterized by the loss of cholinergic and dopaminergic neurons, respectively, in the brain.  A well established but less recognized feature of both of these diseases is the loss of noradrenergic neurons in the brainstem locus coeruleus (LC), the major source of norepinephrine (NE) in the brain.  Cell culture models have revealed that NE can protect neurons in cell culture from death, and animal models have revealed that LC lesions exacerbate both AD and PD-like neuropathology and behavioral deficits.  Thus, it is of interest to determine the role of NE in neurodegenerative disease. We are currently assessing Dbh -/- mice and norepinephrine transporter knockout mice that also carry a transgene expressing mutant beta-amyloid to assess the contribution of NE to AD-like neuropathology and behavioral deficits. In addition, we are using the MPTP model of PD in Dbh -/- mice to understand how NE modulates dopamine neuron death and behavioral deficits in PD. 

Epilepsy and Depression

Although depression is the most common co-morbid condition associated with epilepsy from an epidemiological standpoint, the relationship between these diseases has never been demonstrated experimentally, and possible underlying mechanisms are unclear. The creation of an animal model of epilepsy and depression co-morbidity is essential to understanding the mechanisms of this interaction.  We have recently created an animal model of epilepsy and depression comorbidity by showing that rats selectively bred for depression-like phenotypes also have increased seizure susceptibility. We are currently characterizing these rats further using behavioral pharmacology, electrophysiology, gene mapping, and expression microarrays.


  • BA, Psychobiology, University of California, Santa Cruz, 1987-1992
  • PhD, Genetics, University of Washington, James H. Thomas, Advisor,
  • Postdoctoral Research Fellow, Howard Hughes Medical Institute, University of Washington. Richard D. Palmiter, Advisor,