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Research Description
General
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.
Introduction
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.
Areas of Specialization / Research Interests
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.
Education
1987-1992 B.A. in Psychobiology, University of California, Santa Cruz
1992-1997 Ph. D. in Genetics, University of Washington, James H. Thomas, Advisor
1998-2002 Postdoctoral Research Fellow, Howard Hughes Medical
Institute, University of Washington. Richard D. Palmiter, Advisor
Selected Publications
Szot
P, Weinshenker D, White SS, Robbins CA, Rust NC, Schwartzkroin PA,
Palmiter RD (1999) Norepinephrine-deficient mice have increased
susceptibility to seizure-inducing stimuli. J Neurosci 19:10985-92.
PMID: 10594079.
Weinshenker D, Rust NC, Miller NS, Palmiter RD
(2000) Ethanol-associated behaviors of mice lacking norepinephrine. J
Neurosci 20:3157-3164. PMID: 10777779.
Weinshenker D, Szot P,
Miller NS, Rust NC, White SS Palmiter RD (2001) Genetic Comparison of
Seizure Control by Norepinephrine and Neuropeptide Y. J Neurosci
21:7764-7769. PMID: 11567066.
Weinshenker D, Szot P, Miller NS,
Palmiter RD (2001) 1 and 2 Adrenoreceptor Agonists Inhibit
Pentylenetetrazole-Induced Seizures in Mice Lacking Norepinephrine. J
Pharmacol Exp Ther 298:1042-1048. PMID: 11504801.
Weinshenker D,
White SS, Javors MA, Palmiter RD, Szot P (2002) Regulation of
norepinephrine transporter abundance by catecholamines and desipramine
in vivo. Brain Res 946:239-246. PMID: 12137927. PMID: 12370425
Weinshenker
D, Miller NS, Blizinsky K, Laughlin ML, Palmiter RD (2002) Mice with
chronic norepinephrine deficiency resemble amphetamine-sensitized
animals. Proc Nat Acad Sci USA 99:13873-13877. PMCID: PMC129790.
Szot
P, Lester M, Laughlin ML, Liles LC, Palmiter RD, Weinshenker D (2004)
The anticonvulsant and proconvulsant effects of 2-adrenoreceptor
agonists are mediated by distinct populations of 2A-adrenoreceptors.
Neuroscience 126:795-803. PMID: 15183527.
Rommelfanger K,
Weinshenker D, Miller GW (2004) Reduced MPTP toxicity in norepinephrine
transporter knockout mice. J Neurochem 91:1116-1124. PMID: 15569255.
Marino
MD, Bourdélat-Parks BN, Weinshenker D (2005) Genetic reduction of
noradrenergic function alters social memory and reduces aggression in
mice. Behav Brain Res 161:197-203. PMID: 15922045.
Schank JR,
Liles LC, Weinshenker D (2005) Norepinephrine is required for the full
anticonvulsant effects of valproic acid in mice. Epilepsy Res 65:23-31.
PMID: 15955669.
Weinshenker D, Wilson MM, Williams KM, Weiss JM,
Lamb NE, Twigger SN (2005) A new method for identifying informative
genetic markers in selectively bred rats. Mamm Genome 16:784-791. PMID:
16261420.
Bourdelat-Parks B, Anderson, GM, Donaldson ZR, Weiss
JM, Bonsall RW, Emery MS, Liles LC, Weinshenker D (2005) Effects of
dopamine -hydroxylase genotype and disulfiram inhibition on
catecholamine homeostasis in mice. Psychopharmacology 183:72-80. PMID:
16163519.
Schank JR, Ventura R, Puglisi-Allegra S, Alcaro A, Cole
CD, Liles LC, Seeman P, Weinshenker D (2006) Dopamine -hydroxylase
knockout mice have alterations in dopamine signaling and are
hypersensitive to cocaine. Neuropsychopharmacology 31:2221-2230. PMID:
16395294.
Swoap SJ, Gutilla MJ, Liles LC, Smith RO, Weinshenker D
(2006) The full expression of fasting-induced torpor in mice requires
beta-3 adrenergic receptor signaling. J Neurosci 26:241-245. PMID:
16399693.
Olson VG, Heusner CL, Bland RJ, During MJ, Weinshenker
D, Palmiter RD. (2006) Role of noradrenergic signaling by the nucleus
tractus solitarius in mediating opiate reward. Science 311:1017-1020.
PMID: 16484499.
Ahern T, Javors MA, Eagles DA, Martillotti J,
Mitchell HA, Liles LC, Weinshenker D (2006) The effects of chronic
norepinephrine transporter inactivation on seizure susceptibility in
mice. Neuropsychopharmacology 31:730-738. PMID: 16052243.
Mitchell
HA, Ahern TH, Liles LC, Javors MA, Weinshenker D (2006) The effects of
norepinephrine transporter inactivation on locomotor activity in mice.
Biol Psych 60:1046-1052. PMID: 16893531.
Paladini CA, Beckstead
MJ, Weinshenker D (2007) Electrophysiological properties of
catecholaminergic neurons in the norepinephrine-deficient mouse.
Neuroscience 144:1067-1074. PMCID: PMC1847415.
Tabb KD,
Boss-Williams KA, Weiss JM, Weinshenker D (2007) Rats bred for
susceptibility to depression-like phenotypes have higher kainic
acid-induced seizure mortality than their depression-resistant
counterparts. Epilepsy Res 74:140-146. PMCID: PMC1940038.
Rommelfanger
KS, Edwards GL, Freeman KG, Liles LC, Miller GW, Weinshenker D (2007)
Norepinephrine loss produces more profound motor deficits than MPTP in
mice. Proc Natl Acad Sci USA 104:13804-13809. PMCID: PMC1959463.
Schank
JR, Liles LC, Weinshenker D (2008) Norepinephrine signaling through
-adrenergic receptors is critical for expression of cocaine-induced
anxiety. Biol Psych 63:1007-1012. PMCID: PMC2405894.
Weinshenker
D, Ferrucci M, Busceti CL, Biagioni F, Lazzeri G, Liles LC, Lenzi P,
Pasquali L, Murri L, Paparelli A, Fornai F (2008) Genetic or
pharmacological blockade of noradrenaline synthesis enhances the
neurochemical, behavioural, and neurotoxic effects of methamphetamine. J
Neurochem 105:471-483. PMCID: PMC2610530.
Gaval-Cruz M,
Schroeder JP, Liles LC, Javors MA, Weinshenker D (2008) Effects of
disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced
seizures. Pharmacol Biochem Behav 89:556-562. PMCID: PMC2386143.
Mitchell
HA, Bogenpohl JW, Liles LC, Epstein MP, Bozyczko-Coyne D, Williams M,
Weinshenker D (2008) Behavioral responses of dopamine -hydroxylase
knockout mice to modafinil suggest a dual noradrenergic-dopaminergic
mechanism of action. Pharmacol Biochem Behav 91:217-222. PMCID:
PMC2597705.
Swoap SJ, Weinshenker D (2008) Norepinephrine
controls both torpor initiation and emergence via distinct mechanisms in
the mouse. PLoS One 3:e4038. PMCID: PMC2602851.
Rommelfanger KS,
MItrano DA, Smith Y, Weinshenker D (2009) Light and electron
microscopic localization of alpha-1 adrenergic receptor immunoreactivity
in the rat striatum and ventral midbrain. Neuroscience 158:1530-1540.
PMCID: PMC2692639.
Taylor TN, Caudle WM, Shepherd KR, Noorian A,
Jackson CR, Iuvone PM, Weinshenker D, Greene JG, Miller GW (2009)
Nonmotor symptoms of Parkinson’s disease revealed in an animal model
with reduced monoamine storage capacity. J Neurosci 29:8103-8113. PMCID:
PMC2813143.
Yanpallewar SU, Fernandes K, Marathe SV, Vadodaria
KC, Jhaveri D, Rommelfanger K, Ladiwala U, Jha S, Muthig V, Hein L,
Bartlett P, Weinshenker D, Vaidya VA (2009) 2-adrenoceptor blockade
accelerates the neurogenic, neurotrophic, and behavioral effects of
chronic antidepressant treatment. J Neurosci 30:1096-1109. PMID:
20089918 (PMC in process).
Schroeder JP, Cooper DA, Schank JR,
Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM,
Edwards GL, Holmes PV, Weinshenker D (2010) Disulfiram Attenuates
Drug-Primed Reinstatement of Cocaine Seeking via Inhibition of Dopamine
beta-Hydroxylase. Neuropsychopharmacology [Epub ahead of print 8/25/10]
Review Articles
Weinshenker
D, Szot P (2002) The role of catecholamines in seizure susceptibility:
new results using genetically engineered mice. Pharmacol Ther
94:213-233. PMID: 12113799.
Weinshenker D, Schroeder JP (2006)
There and back again: a tale of norepinephrine and drug addiction.
Neuropsychopharmacology 32:1433-1451. PMID: 17164822.
Rommelfanger
KS, Weinshenker D (2007) Norepinephrine: the redheaded stepchild of
Parkinson’s disease. Biochem Pharmacol 74:177-190. PMID: 17416354.
Weinshenker
D (2008) Functional consequences of locus coeruleus degeneration in
Alzheimer’s disease. Curr Alzheimer Res 5:342-345. PMID: 18537547.
Gaval-Cruz
M, Weinshenker D (2009) mechanisms of disulfiram-induced cocaine
abstinence: antabuse and cocaine relapse. Mol Interv 9:175-187. PMID:
19720750 (PMC in process).
Mitchell HA, Weinshenker D (2010) Good
night and good luck: norepinephrine in sleep pharmacology. Biochem
Pharmacol 79:801-809. PMCID: PMC2812689. |