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Andrew R Tapper PhD

TitleProfessor
InstitutionUniversity of Massachusetts Medical School
DepartmentNeurobiology
AddressBrudnick Neuropsychiatric Research Institute
364 Plantation Street, LRB 605
Worcester MA 01605
Phone774-455-4326
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentNeurobiology

    InstitutionUMMS - School of Medicine
    DepartmentNeuroNexus Institute

    InstitutionUMMS - School of Medicine
    DepartmentPsychiatry

    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


    Collapse Biography 
    Collapse education and training
    University of California, Riverside, Riverside, CA, United StatesBSBiochemistry
    University of California, Riverside, Riverside, CA, United StatesMSBiochemistry
    Vanderbilt University, Nashville, TN, United StatesPHDPharmacology

    Collapse Overview 
    Collapse overview

    The Neurobiology of Addiction and Addiction-related Behaviors


    Our laboratory is interested in elucidating the brain areas, circuits, and molecular mechanisms underlying addiction and addiction-related behaviors.  Toward this goal, we use a multidisciplinary approach that includes optogenetic, biophysical, molecular, and behavioral tools that, to date, have helped uncover novel molecular mechanisms underlying the rewarding properties of nicotine and alcohol, identified brain areas, circuits, and molecular components critical for nicotine withdrawal symptoms, and elucidated circuit-based mechanisms that determine novelty preference, a behavioral trait often associated with addiction. We anticipate that our continuing work will lead to new therapeutic strategies to alleviate addiction.


    The Habenulo-Interpeduncular axis in nicotine dependence.


    Much of our recent work has focused on two understudied and interconnected brain areas, the medial habenula (MHb) and the interpeduncular nucleus (IPN).  The MHb is an epithalamic brain region consisting of substance P expressing neurons on the dorsal side and a dense cluster of cholinergic neurons that can also co-release glutamate on the ventral side.  Bundles of MHb neuron axons, together forming the fasciculus retroflexus (FR), project almost exclusively to the IPN which sits deep within the midbrain ventral and medial to the ventral tegmental area (VTA), the hub of the brain’s “reward” circuitry.  Our lab has discovered that, during nicotine withdrawal, discreet sub-regions of the IPN become activated triggering not only physical symptoms but also increased anxiety during withdrawal, in part, through increased excitatory input from the MHb.  In addition, we have determined that a sub-set of neurons within the VTA project to and innervate the IPN indicating cross-talk between reward- and withdrawal-associated brain areas. Currently, we are characterizing how the VTA and IPN interact and how other IPN-connected brain regions may also control nicotine withdrawal symptoms.


    The Interpeduncular Nucleus in addiction-related behaviors.


    There has been great interest in identifying behavioral/personality traits that may predispose one to addiction. A common trait associated with addiction by epidemiological studies is an increased response to or preference for novel stimuli (i.e. sensation seeking).  In rodent models, rodents with a high novelty preference (NP), defined as more time spent interacting with novel compared to familiar stimuli when given a choice, will work harder to obtain a drug compared to rodents with low NP. We have recently discovered that the IPN is a major node for controlling NP.  We found that IPN inhibitory GABAergic neurons become increasingly activated when we expose mice to the same stimuli multiple times; that is, activation of GABAergic neurons increase as novel stimuli became familiar.  Using optogenetics, we found that we could control an animals’ exploratory activity or interest towards novel or familiar stimuli by activating or silencing GABAergic IPN neurons, which either decreased exploration of novel stimuli or increase exploration of familiar stimuli, respectively.  Thus, activation of IPN GABAergic neurons acts as a brake that reduces exploratory activity towards novel stimuli with repeated exposures.  We went on to map two inputs to the IPN that determine, in part, NP:  MHb excitatory IPN afferents were necessary and sufficient to activate IPN GABAergic neurons during familiarity encounters, while activation of IPN afferents from VTA DAergic neurons could inhibit overall GABAergic activity of the IPN and increase interaction with familiar stimuli during NP.  We are continuing to map the circuitry implicated in controlling the preference for novelty which should yield insights into novel mechanisms that may predict vulnerability to addiction.


     


     


     


     




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Sweeney CG, Kearney PJ, Fagan RR, Smith LA, Bolden NC, Zhao-Shea R, Rivera IV, Kolpakova J, Xie J, Gao G, Tapper AR, Martin GE, Melikian HE. Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function. Neuropsychopharmacology. 2019 Jul 05. PMID: 31277075.
      View in: PubMed
    2. Gunner G, Cheadle L, Johnson KM, Ayata P, Badimon A, Mondo E, Nagy MA, Liu L, Bemiller SM, Kim KW, Lira SA, Lamb BT, Tapper AR, Ransohoff RM, Greenberg ME, Schaefer A, Schafer DP. Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling. Nat Neurosci. 2019 Jun 17. PMID: 31209379.
      View in: PubMed
    3. Klenowski PM, Tapper AR. Molecular, Neuronal, and Behavioral Effects of Ethanol and Nicotine Interactions. Handb Exp Pharmacol. 2018 Feb 09. PMID: 29423839.
      View in: PubMed
    4. Molas S, Zhao-Shea R, Liu L, DeGroot SR, Gardner PD, Tapper AR. A circuit-based mechanism underlying familiarity signaling and the preference for novelty. Nat Neurosci. 2017 Sep; 20(9):1260-1268. PMID: 28714952.
      View in: PubMed
    5. Ji X, Saha S, Kolpakova J, Guildford M, Tapper AR, Martin GE. Dopamine Receptors Differentially Control Binge Alcohol Drinking-Mediated Synaptic Plasticity of the Core Nucleus Accumbens Direct and Indirect Pathways. J Neurosci. 2017 May 31; 37(22):5463-5474. PMID: 28473645.
      View in: PubMed
    6. Vallaster MP, Kukreja S, Bing XY, Ngolab J, Zhao-Shea R, Gardner PD, Tapper AR, Rando OJ. Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring. Elife. 2017 Feb 14; 6. PMID: 28196335.
      View in: PubMed
    7. Ji X, Saha S, Gao G, Lasek AW, Homanics GE, Guildford M, Tapper AR, Martin GE. The Sodium Channel ß4 Auxiliary Subunit Selectively Controls Long-Term Depression in Core Nucleus Accumbens Medium Spiny Neurons. Front Cell Neurosci. 2017; 11:17. PMID: 28243192.
      View in: PubMed
    8. Molas S, DeGroot SR, Zhao-Shea R, Tapper AR. Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis. Trends Pharmacol Sci. 2017 Feb; 38(2):169-180. PMID: 27890353.
      View in: PubMed
    9. Guildford MJ, Sacino AV, Tapper AR. Modulation of ethanol reward sensitivity by nicotinic acetylcholine receptors containing the a6 subunit. Alcohol. 2016 Dec; 57:65-70. PMID: 27793544.
      View in: PubMed
    10. Pang X, Liu L, Ngolab J, Zhao-Shea R, McIntosh JM, Gardner PD, Tapper AR. Habenula cholinergic neurons regulate anxiety during nicotine withdrawal via nicotinic acetylcholine receptors. Neuropharmacology. 2016 Aug; 107:294-304. PMID: 27020042.
      View in: PubMed
    11. Slater CA, Jackson A, Muldoon PP, Dawson A, O'Brien M, Soll LG, Abdullah R, Carroll FI, Tapper AR, Miles MF, Banks ML, Bettinger JC, Damaj IM. Nicotine Enhances the Hypnotic and Hypothermic Effects of Alcohol in the Mouse. Alcohol Clin Exp Res. 2016 Jan; 40(1):62-72. PMID: 26727524.
      View in: PubMed
    12. Shea JM, Serra RW, Carone BR, Shulha HP, Kucukural A, Ziller MJ, Vallaster MP, Gu H, Tapper AR, Gardner PD, Meissner A, Garber M, Rando OJ. Genetic and Epigenetic Variation, but Not Diet, Shape the Sperm Methylome. Dev Cell. 2015 Dec 21; 35(6):750-8. PMID: 26702833.
      View in: PubMed
    13. You IJ, Wright SR, Garcia-Garcia AL, Tapper AR, Gardner PD, Koob GF, David Leonardo E, Bohn LM, Wee S. 5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking. Neuropsychopharmacology. 2016 Apr; 41(5):1210-22. PMID: 26324408.
      View in: PubMed
    14. Zhao-Shea R, DeGroot SR, Liu L, Vallaster M, Pang X, Su Q, Gao G, Rando OJ, Martin GE, George O, Gardner PD, Tapper AR. Corrigendum: Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal. Nat Commun. 2015; 6:7625. PMID: 26133887.
      View in: PubMed
    15. Ngolab J, Liu L, Zhao-Shea R, Gao G, Gardner PD, Tapper AR. Functional Upregulation of a4* Nicotinic Acetylcholine Receptors in VTA GABAergic Neurons Increases Sensitivity to Nicotine Reward. J Neurosci. 2015 Jun 3; 35(22):8570-8. PMID: 26041923.
      View in: PubMed
    16. Zhao-Shea R, DeGroot SR, Liu L, Vallaster M, Pang X, Su Q, Gao G, Rando OJ, Martin GE, George O, Gardner PD, Tapper AR. Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal. Nat Commun. 2015 Apr 21; 6:6770. PMID: 25898242.
      View in: PubMed
    17. Grieder TE, Herman MA, Contet C, Tan LA, Vargas-Perez H, Cohen A, Chwalek M, Maal-Bared G, Freiling J, Schlosburg JE, Clarke L, Crawford E, Koebel P, Repunte-Canonigo V, Sanna PP, Tapper AR, Roberto M, Kieffer BL, Sawchenko PE, Koob GF, van der Kooy D, George O. VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation. Nat Neurosci. 2014 Dec; 17(12):1751-8. PMID: 25402857.
      View in: PubMed
    18. Hogan EM, Casserly AP, Scofield MD, Mou Z, Zhao-Shea R, Johnson CW, Tapper AR, Gardner PD. miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family. RNA. 2014 Dec; 20(12):1890-9. PMID: 25344397.
      View in: PubMed
    19. 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. PMID: 24239118.
      View in: PubMed
    20. 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. PMID: 24184162.
      View in: PubMed
    21. Improgo MR, Soll LG, Tapper AR, Gardner PD. Nicotinic acetylcholine receptors mediate lung cancer growth. Front Physiol. 2013; 4:251. PMID: 24062692.
      View in: PubMed
    22. 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. PMID: 23836290.
      View in: PubMed
    23. 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. PMID: 23811312.
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    24. 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. PMID: 23688922.
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    25. Hendrickson LM, Guildford MJ, Tapper AR. Neuronal nicotinic acetylcholine receptors: common molecular substrates of nicotine and alcohol dependence. Front Psychiatry. 2013; 4:29. PMID: 23641218.
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    26. 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. PMID: 23141806.
      View in: PubMed
    27. 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. PMID: 22222765.
      View in: PubMed
    28. 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. PMID: 21980358.
      View in: PubMed
    29. 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. PMID: 21931655.
      View in: PubMed
    30. Improgo MR, Tapper AR, Gardner PD. Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer. Biochem Pharmacol. 2011 Oct 15; 82(8):1015-21. PMID: 21640716.
      View in: PubMed
    31. 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. PMID: 21239887.
      View in: PubMed
    32. 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. PMID: 21289604.
      View in: PubMed
    33. Scofield MD, Tapper AR, Gardner PD. A transcriptional regulatory element critical for CHRNB4 promoter activity in vivo. Neuroscience. 2010 Nov 10; 170(4):1056-64. PMID: 20696214.
      View in: PubMed
    34. 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. PMID: 20668200.
      View in: PubMed
    35. Improgo MR, Scofield MD, Tapper AR, Gardner PD. From smoking to lung cancer: the CHRNA5/A3/B4 connection. Oncogene. 2010 Sep 2; 29(35):4874-84. PMID: 20581870.
      View in: PubMed
    36. 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. PMID: 20685379.
      View in: PubMed
    37. 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. PMID: 20124469.
      View in: PubMed
    38. 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. PMID: 19720621.
      View in: PubMed
    39. 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. PMID: 19687231.
      View in: PubMed
    40. 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. PMID: 19304657.
      View in: PubMed
    41. 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. PMID: 19247637.
      View in: PubMed
    42. 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. PMID: 18981408.
      View in: PubMed
    43. 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. PMID: 18288092.
      View in: PubMed
    44. 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. PMID: 17712039.
      View in: PubMed
    45. 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. PMID: 15528443.
      View in: PubMed
    46. 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. PMID: 14579512.
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    47. Tapper AR, George AL. Heterologous expression of ion channels. Methods Mol Biol. 2003; 217:285-94. PMID: 12491941.
      View in: PubMed
    48. 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. PMID: 12148092.
      View in: PubMed
    49. Tapper AR, George AL. Location and orientation of minK within the I(Ks) potassium channel complex. J Biol Chem. 2001 Oct 12; 276(41):38249-54. PMID: 11479291.
      View in: PubMed
    50. Tapper AR, George AL. MinK subdomains that mediate modulation of and association with KvLQT1. J Gen Physiol. 2000 Sep; 116(3):379-90. PMID: 10962015.
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    51. Morrow JD, Tapper AR, Zackert WE, Yang J, Sanchez SC, Montine TJ, Roberts LJ. Formation of novel isoprostane-like compounds from docosahexaenoic acid. Adv Exp Med Biol. 1999; 469:343-7. PMID: 10667351.
      View in: PubMed
    52. Roberts LJ, Montine TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob S, Dettbarn WD, Morrow JD. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem. 1998 May 29; 273(22):13605-12. PMID: 9593698.
      View in: PubMed
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