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Professor of Pharmacology
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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: Daniel DeGuisto, David Perry, Linda Lomazzo, Menahem Doura, Bethany Hoegberg
- Neuronal nicotinic receptors; nicotinic neurobiology; nicotine addiction; drugs of abuse; autoradiography
My lab studies the neurobiology of nicotine. The use of tobacco products is the biggest preventable cause of disease and death in this country. Nicotine is the primary psychoactive compound in tobacco, and nicotine addiction is the driving force behind the continued widespread use of tobacco products, given that the detrimental effects of these products are well-known. The research in my lab is funded by grants from the National Institute on Drug Abuse (NIDA).
Effects of Chronic Nicotine on Nicotinic Receptors. In collaboration with Dr. Ken Kellar of Georgetown, we study how chronic exposure to nicotine (such as occurs in smokers) affects receptors for nicotine. Nicotinic receptors mediate the effects of the neurotransmitter acetylcholine; different subtypes of nicotinic receptors consist of different combinations of α and β subunit proteins. Using quantitative autoradiography, we showed that the α4β2* subtype, the most abundant receptor in mammalian CNS, is up-regulated (increased) after chronic exposure to nicotine differentially across brain regions. These up-regulated receptors are in fact functional, as demonstrated by rubidium efflux to assess channel function.
Subsequent studies revealed that nicotine’s effects on CNS nicotinic receptors are more complex and subtle than originally thought. For instance, á6â2* receptors are actually down-regulated by chronic nicotine. This subtype is important because of its location in the brains’ dopamine “reward pathway”. The down-regulation of á6â2* receptors by chronic nicotine correlates closely to a decrease in their ability to stimulate dopamine release. Furthermore, inclusion of certain subunit proteins in these receptors can further change nicotine’s effects. For instance, the á4â2 receptor, which is strongly up-regulated by chronic nicotine, is unaffected if it also contains the á5 subunit. Similarly, while á6â2 receptors are down-regulated by chronic nicotine, a subset of these receptors that also contain the â3 subunit is not down-regulated.
Why is Receptor Up- and Down-Regulation Important? As we and others have shown, receptor regulation by nicotine is not just a lab phenomenon, but occurs in human smokers as well, to an even greater extent than in rodents. The different subtypes of nicotinic cholinergic receptors mediate our brain’s response to acetylcholine signaling, which plays critical roles in many functions such as learning and memory. In a smoker’s brain, the complement of different nicotinic receptor subtypes is altered by this complex mixture of up- and down-regulation in the various brain regions, and thus smokers will have an altered pattern of response to normal cholinergic signaling, and also to drugs such as nicotine. This altered response also is likely to contribute to nicotine addiction, which makes this an important public health issue.
Pregnant Smokers Smoking rates in pregnant women remain as high as 15%, despite the knowledge that this is associated with a host of detrimental outcomes in offspring, from low birth weight and SIDS to behavioral deficits such as ADHD. My lab is collaborating with researchers from the GW School of Public Health (NIH-DC Initiative to Reduce Infant Mortality Among Minority Populations) in a trial testing the efficacy of nicotine patches for smoking cessation in pregnant women in the District of Columbia; results from these studies are due to be published soon. We are also examining for unique effects of prenatal nicotine exposure in our rat model. Our initial studies found that prenatal exposure caused persistent effects in CNS nicotinic receptors that led to an altered response to nicotine challenge in adolescent offspring.
Adolescent Smokers 
Smokers who begin their habit as young teenagers have a much more difficult time quitting, and a higher likelihood of dependence to other drugs of abuse in adulthood. We demonstrated significant differences between adult and adolescent rat brains in the numbers of three major subtypes of nicotinic receptors and in their response to chronic nicotine. In collaboration with Dr. Norman Lee of GWUMC, our current studies compare the effects of chronic nicotine in adolescents and adults on gene expression in an integral part of the brain’s reward pathway. In the adult, most of nicotine’s effects on gene regulation were transient (i.e. they were detectable immediately after nicotine exposure, but did not remain one month later). In contrast, adolescent rats had fewer transiently altered genes, but far more (up to 5 times) genes that were persistently regulated—their expression remained altered one month after the end of nicotine exposure. These persistently altered genes included some for neuronal development, as well as genes involved in learning and memory. These results suggest that exposure to nicotine while the brain is still developing can have profound and lasting effects on gene expression in the brain’s reward pathway, that persist at least until adulthood, whereas adult exposure is far less likely to have such persistent effects. We believe these findings may have profound consequences on our understanding of adolescent smoking and drug abuse in general.
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. Rasmussen BA, O'Neil J, Manaye KF, Perry DC, Tizabi Y (2006) Long-term effects of developmental PCP administration on sensorimotor gating in male and female rats. Psychopharmacology (Berl). 190: 43-9.
Perry DC, Mao D, Gold AB, McIntosh JM, Pezzullo JC, & Kellar KJ. (2007) Chronic nicotine differentially regulates alpha6- and beta3-containing nicotinic cholinergic receptors in rat brain.J Pharmacol Exp Ther. 322:306-15.
Mao D, Perry DC, Yasuda RP, Wolfe BB & Kellar KJ. (2008) The alpha4beta2alpha5 nicotinic cholinergic receptor in rat brain is resistant to up-regulation by nicotine in vivo. J Neurochem. 104:446-56
Cox BC, Marritt AM, Perry DC, Kellar KJ (2008). Transport of multiple nicotinic acetylcholine receptors in the rat optic nerve: high densities of receptors containing alpha6 and beta3 subunits.
J Neurochem. 105: 1924-38.
Doura MB, Gold AB, Keller AB & Perry DC. (2008) Adult and periadolescent rats differ in expression of nicotinic cholinergic receptor subtypes and in the response of these subtypes to chronic nicotine exposure. Brain Res. 1215:40-52
Rasmussen BA, Perry DC, O'Neil J, Manaye KF, Tizabi Y (2008) Effects of nicotine on sensorimotor gating impairment induced by long-term treatment with neurotoxic NMDA antagonism. Neurotox Res. 13:151-61.
Gold AB, Keller AB, Perry DC (2009) Prenatal exposure of rats to nicotine causes persistent alterations of nicotinic cholinergic receptors. Brain Res. 1250: 88-100.
Pearson J, Windsor R, El-Mohandes A & Perry DC (2009 Evaluation of the immediate impact of the Washington, D.C., smoke-free indoor air policy on bar employee environmental tobacco smoke exposure. Public Health Reports 124 Supp. 1: 135-142.
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a Medline search for other publications of Dr. Perry’s, click HERE
