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Professor of Pharmacology
The George Washington University Medical Center
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Department of Pharmacology & Physiology, Ross 618 2300 Eye St. NW Washington DC. 20037 Email Dr. Perry Voice: 202-994-3544 Fax:202-994-2870 |
| Affiliation Links | Additional Links |
- B.A. in Biochemical Sciences, Harvard College, 1970
- Ph.D. in Pharmaceutical Chemistry, University of California, San Francisco, 1981
- Postdoctoral fellowship in Neuroscience, Johns Hopkins (lab of Dr. Solomon H. Snyder), 1983
Left to Right: Ashleigh Keller, Allison Gold, David Perry, Menahem Doura, Siva Balasubramanian (Biology)
- Neuronal nicotinic receptors; nicotinic neurobiology; nicotine addiction; drugs of abuse; autoradiography
The
research in my lab is aimed at understanding the roles of neuronal nicotinic
cholinergic receptors in neurotransmission, disease and in mediating nicotine
addiction. Of particular interest to us is elucidating how different
subtypes of nicotinic receptors contribute to these processes. Our
principal effort recently has been in receptor autoradiography. Along
with Dr.
Ken Kellar of Georgetown University, we pioneered
the use of several new radioligands to label nicotinic receptors, including
[3H]epibatidine, [125I]epibatidine and [125I]A-85380.
By combining our knowledge of how these ligands bind to receptor subunits
expressed in clonal cell lines, with their pattern of labeling in brain
sections, we have developed a novel quantitative approach to measure receptor
subtypes with autoradiography. This method allows us to measure different
subtypes even in small nuclei in the brain and other tissues; using this
approach in rat, we have detected not only the major subtypes of a4b2*
and a7, but also subtypes with a more limited
distribution, including one with properties of a3b4*
receptors and another with properties of a3/a6b2*
receptors.
An important approach to understanding nicotine addiction is to study the effects of chronic
nicotine administration on the brain. We used autoradiographic methods
to demonstrate that nicotinic receptors are greatly up-regulated in brains
from human smokers (see figure above). This up-regulation may help
mediate the neurobiological changes associated with nicotine addiction.
We have recently applied our new quantitative autoradiographic methods
to show that subtypes of nicotinic receptors are differentially affected
by chronic nicotine in rat brain. This may contribute to an altered
pattern of response of experienced smokers compared to naive users. Our
recent studies with Dr. Kellar have demonstrated that while a4b2
subtypes
are readily upregulated, inclusion of an a5
subunit
along with a4 and b2
blocks upregulation by nicotine. Also with Dr. Kellar, we have now
shown that receptors containing the a6
subunit
are actually down-regulated in some brain regions. There is controversy
over whether up-regulated nicotinic receptors correspond to an increase
in functional activity, or whether they are composed largely of inactivated
receptor sites. To address this question, we employed the rubidium
efflux method to measure changes in receptor function following chronic
nicotine exposure. We found that while exposure to nicotine overnight
had no effect, two week exposure caused an increase in rubidium efflux
in some regions (cerebral cortex, superior colliculus), but no change in
others. This increased functional activity appeared to be largely
limited to the a4b2
subtype. Similarly, the down-regulation of a6*
receptors in striatum corresponds
to a decreased ability of nicotine to stimulate release of dopamine in
that region. Our current studies are
focused on extending these findings to determine the onset of these changes
and the rate of recovery. We are also interested in the changes in
gene expression that occur during chronic nicotine exposure. In particular,
we are studying whether there are differences between adults and adolescents
in their response to chronic nicotine.
Neuronal nicotinic receptors play a variety of important roles, in both physiological and pathological states. For instance, the very high rate of smoking among schizophrenics is one piece of evidence for a role for nicotinic receptors in this disease. Other areas of interest include nicotine and tobacco use in pregnancy, in collaboration with the GW School of Public Health and the NIH/DC Initiative to Reduce Infant Mortality in Minority Populations.
Davila-Garcia MI, Musachio JL, Perry DC, Xiao Y, Horti A, London ED, Dannals RF & Kellar KJ (1997) [125I]IPH, an epibatidine analog, binds with high affinity to neuronal nicotinic cholinergic receptors. J. Pharmacol. Exp. Therap. 82:445-451.
Perry DC, Dávila-García MI, Stockmeier CA & Kellar KJ (1999) Increased nicotinic receptors in brains from smokers: membrane binding and autoradiographic studies. J. Pharmacol. Exp. Therap. 289:1545-1552.
Tizabi Y, Russell, LT, Nespor SM, Perry DC & Grunberg NE (2000) Prenatal nicotine exposure: Effects on locomotor activity and central [125I]a-bungarotoxin binding in rats. Pharm. Biochem Behav. 66:495-500.
Perry DC, Xiao Y, Nguyen HN, Musachio JL, Davila-Garcia MI & Kellar KJ, (2002) Measuring nicotinic receptors with characteristics of a4â2, a3â2 and a3â4 subtypes in rat tissues by autoradiography. J. Neurochemistry 82:468-481.
Nguyen HN, Rasmussen BE & Perry DC. (2003) Subtype-selective upregulation by chronic nicotine of high affinity nicotinic receptors in rat brain demonstrated by receptor autoradiography. J. Pharmacol. Exp. Therap. 307:1090-1097.
Nguyen HN, Rasmussen BE & Perry DC. (2004) Binding and functional activity of nicotinic cholinergic receptors in selected rat brain regions are increased following long-term but not short-term nicotine treatment J. Neurochemistry 90:40-49
Rasmussen BA, Perry DC. (2006) An autoradiographic analysis of [125I]a-bungarotoxin binding in rat brain after chronic nicotine exposure. Neurosci. Lett. 404:9-14.
For
a Medline search for other publications of Dr. Perry’s, click HERE
