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    Andrew R Tapper PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentPsychiatry
    AddressUniversity of Massachusetts Medical School
    303 Belmont Street
    Worcester MA 01605
    Phone508-856-8164
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBrudnick Neuropsychiatric Research Institute

        Overview 
        Narrative

        Academic Background:

        B.S. Universityof California, Riverside 1995
        M.S. University of California, Riverside 1996
        Ph.D. Vanderbilt University2001

        Postdoctoral Scholar 2002-2006
        Department of Biology
        California Institute of Technology

        Assistant Professor 2006-present
        Department of Psychiatry
        University of MassachusettsMedical School

        Neuronal nicotinic acetylcholine receptors in addiction and neurological disease.

        Dr. Andrew Tapper
        Nicotine addiction elicited by smoking tobacco is responsible for over 3 million deaths annually making it the largest cause of preventable mortality in the world. Nicotine is a naturally occurring alkaloid found in tobacco and is the primary addictive component of cigarette smoke. Vaporized nicotine is rapidly absorbed through the lungs where it enters the blood stream. Within seconds of inhaling, nicotine base readily crosses the blood-brain barrier where it gains access to neuronal nicotinic acetylcholine receptors (nAChRs) expressed throughout the central nervous system (CNS). In its protonated form, nicotine mimics the endogenous neurotransmitter, acetylcholine, and can activate nAChRs, utilizing the cholinergic system which, under normal conditions, plays an important role in reward, anxiety, cognition, attention, and many other physiological processes. This ability of nicotine to “hijack” nAChRs is thought to underlie the molecular basis of nicotine addiction.

        What are nicotinic acetylcholine receptors?

        Neuronal nAChRs are ligand gated cation-selective ion channels that, when activated, can depolarize and activate neurons, as well as modulate neurotransmitter release. Currently, 12 neuronal nicotinic acetylcholine receptor subunits have been identified (a2-10 andb 2-4). The majority of subunits form functional heteromeric pentamers while a subset may form homomeric receptors. Thus, a myriad of nAChR subtypes exist.

        Neuronal nAChRs in nicotine addiction.

        It is becoming increasingly clear that nicotine dependence begins with activation of nAChRs. However, which nAChR subtypes are involved in the addictive properties of nicotine? Recent work has highlighted the idea that different subtypes may mediate different dependence-related behaviors. For example, activation of one particular nAChR subtype may be responsible for the rewarding properties of nicotine whereas chronic activation of a separate subtype may be responsible for withdrawal symptoms upon nicotine cessation. A primary goal of our lab is to identify specific nAChR subtypes critical for behaviors associated with addiction including reward, tolerance, sensitization, and withdrawal.

        Acute nicotine exposure elicits many physiological effects including reward, hypothermia, and, at high enough concentrations, seizures. However, smokers expose themselves to nicotine chronically. It is this chronic exposure that produces long term physiological and behavioral changes associated with dependence. A second goal of our lab is to identify circuits and gene products that undergo adaptations because of chronic nAChR activation (or desensitization) and trigger a nicotine dependent state.

        Neuronal nAChRs in the regulation of dopamine neurotransmission.

        Parkinson’s disease (PD) is a devastating movement disorder that affects approximately one percent of the population over the age of 60. The disease is characterized by slowness of movement (bradykinesia), rigidity, and resting tremor. PD is caused by the disruption of dopamine release in basal ganglia due to the progressive death of dopaminergic neurons in substantia nigra. The reason for this neuronal loss is unknown. To date, the predominant PD treatment is L-dopa, an isomer to the precursor of dopamine (DA) that is used to boost remaining DA release in surviving DAergic neurons. Because of L-dopa’s fading efficacy over time, more recent research has focused on identifying neuroprotective agents that promote midbrain DAergic neuron survival. Remarkably, strong epidemiological data indicates PD is less prevalent in smokers. In addition, animal studies have found that nicotine, the addictive component of tobacco smoke, protects DAergic neurons from chemical insult. Thus, nicotine has emerged as a potential neuroprotective agent in PD. An additional goal of the lab is to understand how nicotinic receptors regulate dopamine neurotransmission in brain regions implicated in Parkinson’s disease.



        Rotation Projects

        Rotation Projects:

        1. Identify the role of specific nicotinic receptor subtypes in nicotine withdrawal. This project combines novel rodent models of nicotine dependence and incorporates behavior, pharmacology, and neurophysiology to understand withdrawal.

        2. There is mounting evidence that nicotinic acetylcholine receptors are involved in other forms of drug addiction besides nicotine. A second project involves determining the role of nAChRs in mediating the addictive properties of alcohol, cocaine, and heroin.

        Because of their wide distribution in the CNS, neuronal nAChRs have been linked to a variety of neurological diseases ranging from Parkinson’s disease to depression to epilepsy. Additional rotation projects are available to elucidate the function of nicotinic receptors in these neurological conditions.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Zhao-Shea R, Liu L, Pang X, Gardner PD, Tapper AR. Activation of GABAergic neurons in the interpeduncular nucleus triggers physical nicotine withdrawal symptoms. Curr Biol. 2013 Dec 2; 23(23):2327-35.
          View in: PubMed
        2. Pang X, Hogan EM, Casserly A, Gao G, Gardner PD, Tapper AR. Dicer expression is essential for adult midbrain dopaminergic neuron maintenance and survival. Mol Cell Neurosci. 2014 Jan; 58:22-8.
          View in: PubMed
        3. Improgo MR, Soll LG, Tapper AR, Gardner PD. Nicotinic acetylcholine receptors mediate lung cancer growth. Front Physiol. 2013; 4:251.
          View in: PubMed
        4. Almeida S, Gascon E, Tran H, Chou HJ, Gendron TF, Degroot S, Tapper AR, Sellier C, Charlet-Berguerand N, Karydas A, Seeley WW, Boxer AL, Petrucelli L, Miller BL, Gao FB. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol. 2013 Sep; 126(3):385-99.
          View in: PubMed
        5. Liu L, Zhao-Shea R, McIntosh JM, Tapper AR. Nicotinic acetylcholine receptors containing the a6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons. Biochem Pharmacol. 2013 Oct 15; 86(8):1194-200.
          View in: PubMed
        6. Soll LG, Grady SR, Salminen O, Marks MJ, Tapper AR. A role for a4(non-a6)* nicotinic acetylcholine receptors in motor behavior. Neuropharmacology. 2013 Oct; 73:19-30.
          View in: PubMed
        7. Hendrickson LM, Guildford MJ, Tapper AR. Neuronal nicotinic acetylcholine receptors: common molecular substrates of nicotine and alcohol dependence. Front Psychiatry. 2013; 4:29.
          View in: PubMed
        8. Liu L, Hendrickson LM, Guildford MJ, Zhao-Shea R, Gardner PD, Tapper AR. Nicotinic acetylcholine receptors containing the a4 subunit modulate alcohol reward. Biol Psychiatry. 2013 Apr 15; 73(8):738-46.
          View in: PubMed
        9. Liu L, Zhao-Shea R, McIntosh JM, Gardner PD, Tapper AR. Nicotine persistently activates ventral tegmental area dopaminergic neurons via nicotinic acetylcholine receptors containing a4 and a6 subunits. Mol Pharmacol. 2012 Apr; 81(4):541-8.
          View in: PubMed
        10. Armata HL, Shroff P, Garlick DE, Penta K, Tapper AR, Sluss HK. Loss of p53 Ser18 and Atm results in embryonic lethality without cooperation in tumorigenesis. PLoS One. 2011; 6(9):e24813.
          View in: PubMed
        11. Improgo MR, Johnson CW, Tapper AR, Gardner PD. Bioluminescence-based high-throughput screen identifies pharmacological agents that target neurotransmitter signaling in small cell lung carcinoma. PLoS One. 2011; 6(9):e24132.
          View in: PubMed
        12. Improgo MR, Tapper AR, Gardner PD. Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer. Biochem Pharmacol. 2011 Oct 15; 82(8):1015-21.
          View in: PubMed
        13. Hendrickson LM, Gardner P, Tapper AR. Nicotinic acetylcholine receptors containing the a4 subunit are critical for the nicotine-induced reduction of acute voluntary ethanol consumption. Channels (Austin). 2011 Mar-Apr; 5(2):124-7.
          View in: PubMed
        14. Zhao-Shea R, Liu L, Soll LG, Improgo MR, Meyers EE, McIntosh JM, Grady SR, Marks MJ, Gardner PD, Tapper AR. Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. Neuropsychopharmacology. 2011 Apr; 36(5):1021-32.
          View in: PubMed
        15. Hendrickson LM, Zhao-Shea R, Pang X, Gardner PD, Tapper AR. Activation of alpha4* nAChRs is necessary and sufficient for varenicline-induced reduction of alcohol consumption. J Neurosci. 2010 Jul 28; 30(30):10169-76.
          View in: PubMed
        16. Improgo MR, Scofield MD, Tapper AR, Gardner PD. The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer. Prog Neurobiol. 2010 Oct; 92(2):212-26.
          View in: PubMed
        17. Improgo MR, Schlichting NA, Cortes RY, Zhao-Shea R, Tapper AR, Gardner PD. ASCL1 regulates the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. Mol Cancer Res. 2010 Feb; 8(2):194-203.
          View in: PubMed
        18. Zhao-Shea R, Cohen BN, Just H, McClure-Begley T, Whiteaker P, Grady SR, Salminen O, Gardner PD, Lester HA, Tapper AR. Dopamine D2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive {alpha}4 nicotinic receptors via a cholinergic-dependent mechanism. FASEB J. 2010 Jan; 24(1):49-57.
          View in: PubMed
        19. Vanoye CG, Welch RC, Daniels MA, Manderfield LJ, Tapper AR, Sanders CR, George AL. Distinct subdomains of the KCNQ1 S6 segment determine channel modulation by different KCNE subunits. J Gen Physiol. 2009 Sep; 134(3):207-17.
          View in: PubMed
        20. Mou Z, Tapper AR, Gardner PD. The armadillo repeat-containing protein, ARMCX3, physically and functionally interacts with the developmental regulatory factor Sox10. J Biol Chem. 2009 May 15; 284(20):13629-40.
          View in: PubMed
        21. Hendrickson LM, Zhao-Shea R, Tapper AR. Modulation of ethanol drinking-in-the-dark by mecamylamine and nicotinic acetylcholine receptor agonists in C57BL/6J mice. Psychopharmacology (Berl). 2009 Jul; 204(4):563-72.
          View in: PubMed
        22. Martin GE, Hendrickson LM, Penta KL, Friesen RM, Pietrzykowski AZ, Tapper AR, Treistman SN. Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol. Proc Natl Acad Sci U S A. 2008 Nov 11; 105(45):17543-8.
          View in: PubMed
        23. Schroeder FA, Penta KL, Matevossian A, Jones SR, Konradi C, Tapper AR, Akbarian S. Drug-induced activation of dopamine D(1) receptor signaling and inhibition of class I/II histone deacetylase induce chromatin remodeling in reward circuitry and modulate cocaine-related behaviors. Neuropsychopharmacology. 2008 Nov; 33(12):2981-92.
          View in: PubMed
        24. Tapper AR, McKinney SL, Marks MJ, Lester HA. Nicotine responses in hypersensitive and knockout alpha 4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice. Physiol Genomics. 2007 Nov 14; 31(3):422-8.
          View in: PubMed
        25. Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P, Labarca C, Whiteaker P, Marks MJ, Collins AC, Lester HA. Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science. 2004 Nov 5; 306(5698):1029-32.
          View in: PubMed
        26. Lester HA, Fonck C, Tapper AR, McKinney S, Damaj MI, Balogh S, Owens J, Wehner JM, Collins AC, Labarca C. Hypersensitive knockin mouse strains identify receptors and pathways for nicotine action. Curr Opin Drug Discov Devel. 2003 Sep; 6(5):633-9.
          View in: PubMed
        27. Tapper AR, George AL. Heterologous expression of ion channels. Methods Mol Biol. 2003; 217:285-94.
          View in: PubMed
        28. Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL, Benson DW. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002 Sep; 71(3):663-8.
          View in: PubMed
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