Advertisement

Psychopharmacology

, Volume 235, Issue 4, pp 1151–1161 | Cite as

Negative allosteric modulation of alpha 5-containing GABAA receptors engenders antidepressant-like effects and selectively prevents age-associated hyperactivity in tau-depositing mice

  • Nina Z. Xu
  • Margot Ernst
  • Marco Treven
  • Rok Cerne
  • Mark Wakulchik
  • Xia Li
  • Timothy M. Jones
  • Scott D. Gleason
  • Denise Morrow
  • Jeffrey M. Schkeryantz
  • Md. Toufiqur Rahman
  • Guanguan Li
  • Michael M. Poe
  • James M. Cook
  • Jeffrey M. Witkin
Original Investigation

Abstract

Rationale

Associated with frank neuropathology, patients with Alzheimer’s disease suffer from a host of neuropsychiatric symptoms that include depression, apathy, agitation, and aggression. Negative allosteric modulators (NAMs) of α5-containing GABAA receptors have been suggested to be a novel target for antidepressant action. We hypothesized that pharmacological modulation of this target would engender increased motivation in stressful environments.

Methods

We utilized electrophysiological recordings from Xenopus oocytes and behavioral measures in mice to address this hypothesis.

Results

In the forced-swim assay in mice that detects antidepressant drugs, the α5β3γ2 GABAΑ receptor NAM, RY-080 produced a marked antidepressant phenotype. Another compound, PWZ-029, was characterized as an α5β3γ2 receptor NAM of lower intrinsic efficacy in electrophysiological studies in Xenopus oocytes. In contrast to RY-080, PWZ-029 was only moderately active in the forced-swim assay and the α5β3γ2 receptor antagonist, Xli-093, was not active at all. The effects of RY-080 were prevented by the non-selective benzodiazepine receptor antagonist flumazenil as well as by the selective ligands, PWZ-029 and Xli-093. These findings demonstrate that this effect of RY-080 is driven by negative allosteric modulation of α5βγ2 GABAA receptors. RY-080 was not active in the tail-suspension test. We also demonstrated a reduction in the age-dependent hyperactivity exhibited by transgenic mice that accumulate pathological tau (rTg4510 mice) by RY-080. The decrease in hyperactivity by RY-080 was selective for the hyperactivity of the rTg4510 mice since the locomotion of control strains of mice were not significantly affected by RY-080.

Conclusions

α5βγ2 GABAA receptor NAMs might function as a pharmacological treatment for mood, amotivational syndromes, and psychomotor agitation in patients with Alzheimer’s and other neurodegenerative disorders.

Keywords

Alpha 5-containing GABAA receptors Antidepressant Tau-Depositing Mice Agitation rTg4510 mice 

Abbreviations

β-CCE

3-carboethoxy-beta-carboline

L655,708

ethyl (13aS)-7-methoxy-9-oxo-11,12,13,13a–tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate

MRK-016

3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine

PWZ-029

8-chloro-3-(methoxymethyl)-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one

RO4938581

(3-bromo-10-(difluoromethyl)-9H–benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine)

RY-080

ethyl 8-ethynyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

XLi-093

Bis[8-ethynyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid] 1,3-propanediyl ester hydrate

Notes

Acknowledgments

We thank the following granting agencies for support: MH-096463 and NS-076517, as well as the Austrian Science Fund (FWF I2306). We also acknowledge UW-Milwaukee’s Shimadzu Laboratory for Advanced and Applied Analytical Chemistry and support from the Milwaukee Institute of Drug Discovery and the University of Wisconsin Research Foundation.

We are grateful for Trace Murray of the Neuroscience Discovery Group of the Lilly Research Labs for her gracious help in obtaining the rTg4510 mice. We acknowledge excellent technical assistance by Raphael Holzinger.

Author contributions

Participated in research design: J. M. Witkin, S. D. Gleason, T. M. Jones, R. Cerne, M, Wakulchik, and M. Ernst.

Conducted experiments: JM Witkin, SD Gleason, M, Wakulchik, and M. Treven.

Contributed new reagents or analytic tools: K. R. Methuku2, R. Cerne, J.W. Cramer, T.M. Jones, M. M. Poe, G. Li, L. A. Arnold, J. M. Schkeryantz1, and J. M. Cook2.

Performed data analysis: JM Witkin, SD Gleason, R. Cern, M. Ernst, and M. Treven.

Wrote or contributed to the writing of the manuscript: All authors.

References

  1. Andreeva TV, Lukiw WJ, Rogaev EI (2017) Biological Basis for amyloidogenesis in Alzheimer’s disease. Biochemistry (Mosc) 82(2):122–139.  https://doi.org/10.1134/S0006297917020043 CrossRefGoogle Scholar
  2. Atack JR, Bayley PJ, Fletcher SR, McKernan RM, Wafford KA, Dawson GR (2006a) The proconvulsant effects of the GABAA alpha5 subtype-selective compound RY-080 may not be alpha5-mediated. Eur J Pharmacol 548(1-3):77–82.  https://doi.org/10.1016/j.ejphar.2006.02.055 CrossRefPubMedGoogle Scholar
  3. Atack JR, Bayley PJ, Seabrook GR, Wafford KA, McKernan RM, Dawson GR (2006b) L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors. Neuropharmacology 51(6):1023–1029.  https://doi.org/10.1016/j.neuropharm.2006.04.018 CrossRefPubMedGoogle Scholar
  4. Atack JR, Maubach KA, Wafford KA, O'Connor D, Rodrigues AD, Evans DC, Tattersall FD, Chambers MS, MacLeod AM, Eng WS, Ryan C, Hostetler E, Sanabria SM, Gibson RE, Krause S, Burns HD, Hargreaves RJ, Agrawal NGB, McKernan RM, Murphy MG, Gingrich K, Dawson GR, Musson DG, Petty KJ (2009) In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist. J Pharmacol Exp Ther 331(2):470–484.  https://doi.org/10.1124/jpet.109.157636 CrossRefPubMedGoogle Scholar
  5. Bai F, Li X, Clay M, Lindstrom T, Skolnick P (2001) Intra- and interstrain differences in models of “behavioral despair”. Pharmacol Biochem Behav 70:187–192CrossRefPubMedGoogle Scholar
  6. Ballard TM, Knoflach F, Prinssen E, Borroni E, Vivian JA et al (2009) RO4938581, a novel cognitive enhancer acting at GABAA α5 subunit-containing receptors. Psychopharmacology 202:207–223CrossRefPubMedGoogle Scholar
  7. Behlke LM, Foster RA, Liu J, Benke D, Benham RS, Nathanson AJ, Yee BK, Zeilhofer HU, Engin E, Rudolph U (2016) A pharmacogenetic ‘restriction-of-function’ approach reveals evidence for anxiolytic-like actions mediated by α5-containing gabaa receptors in mice. Neuropsychopharmacology 41(10):2492–2501.  https://doi.org/10.1038/npp.2016.49 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Carreno FR, Collins GT, Frazer A, Lodge DJ (2017) Selective pharmacological augmentation of hippocampal activity produces a sustained antidepressant-like response without abuse-related or psychotomimetic effects. Int J Neuropsychopharmacol 20(6):504–509.  https://doi.org/10.1093/ijnp/pyx003 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Clayton T, Poe MM, Rallapalli S, Biawat P, Savić MM, Rowlett JK, Gallos G, Emala CW, Kaczorowski CC, Stafford DC, Arnold LA, Cook JM (2015) A review of the updated pharmacophore for the alpha 5 GABA(a) benzodiazepine receptor model. Int J Med Chem 2015:1–54.  https://doi.org/10.1155/2015/430248 Google Scholar
  10. Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Otu FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Whiting PJ, Rosahl TW (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 22(13):5572–5580PubMedGoogle Scholar
  11. Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245CrossRefPubMedGoogle Scholar
  12. Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM (2015) Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of alpha5-containing GABAA receptors. Neuropsychopharmacology 40(11):2499–2509.  https://doi.org/10.1038/npp.2015.112 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gehlert DR, Rasmussen K, Shaw J, Li X, Ardayfio P, Craft L, Coskun T, Zhang HY, Chen Y, Witkin JM (2009) Preclinical evaluation of melanin-concentrating hormone receptor 1 antagonism for the treatment of obesity and depression. J Pharmacol Exp Ther 329(2):429–438.  https://doi.org/10.1124/jpet.108.143362 CrossRefPubMedGoogle Scholar
  14. Hajós M, Hoffmann WE, Orbán G, Kiss T, Erdi P (2004) Modulation of septo-hippocampal theta activity by GABAA receptors: an experimental and computational approach. Neuroscience 126(3):599–610.  https://doi.org/10.1016/j.neuroscience.2004.03.043 CrossRefPubMedGoogle Scholar
  15. Hevers W, Lüddens H (1998) The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes. Mol Neurobiol 18(1):35–86.  https://doi.org/10.1007/BF02741459 CrossRefPubMedGoogle Scholar
  16. Hohman TJ, Beason-Held LL, Resnick SM (2011) Cognitive complaints, depressive symptoms, and cognitive impairment: are they related? J Am Geriatr Soc 59(10):1908–1912.  https://doi.org/10.1111/j.1532-5415.2011.03589.x CrossRefPubMedPubMedCentralGoogle Scholar
  17. Hunkeler W, Möhler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290(5806):514–516.  https://doi.org/10.1038/290514a0 CrossRefPubMedGoogle Scholar
  18. Jessen F, Amariglio RE, Van Boxtel M et al (2014) A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease. Alzheimer’s and Dementia 10:844–852CrossRefPubMedPubMedCentralGoogle Scholar
  19. Jul P, Volbracht C, de Jong IE, Helboe L, Elvang AB, Pedersen JT (2015) Hyperactivity with agitative-like behavior in a mouse tauopathy model. J Alzheimers Dis 49(3):783–795.  https://doi.org/10.3233/JAD-150292 CrossRefGoogle Scholar
  20. Leão AHFF, Cabral A, Izídio GS, Ribeiro AM, Silva RH (2016) Diazepam effects on aversive memory retrieval and extinction: role of anxiety levels. Pharmacol Biochem Behav 141:42–49.  https://doi.org/10.1016/j.pbb.2015.11.012 CrossRefPubMedGoogle Scholar
  21. Lewter LA, Fisher JL, Siemian JN, Methuku KR, Poe MM, Cook JM, Li JX (2017) Antinociceptive effects of a novel α2/α3-subtype selective GABAA receptor positive allosteric modulator. ACS Chem Neurosci 8(6):1305–1312.  https://doi.org/10.1021/acschemneuro.6b00447 CrossRefPubMedGoogle Scholar
  22. Li X, Witkin JM, Nead AB, Skolnick P (2003) Enhancement of antidepressant potency by a potentiator of AMPA receptors. Cell Mol Neurobiol 23(3):419–430.  https://doi.org/10.1023/A:1023648923447 CrossRefPubMedGoogle Scholar
  23. Li X, Need AB, Baez M, Witkin JM (2006) mGlu5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharmacol Exp Ther 319(1):254–259.  https://doi.org/10.1124/jpet.106.103143 CrossRefPubMedGoogle Scholar
  24. Liu CS, Ruthirakuhan M, Chau SA, Herrmann N, Carvalho AF, Lanctôt KL (2016) Pharmacological management of agitation and aggression in Alzheimer’s disease: a review of current and novel treatments. Curr Alzheimer Res 13(10):1134–1144.  https://doi.org/10.2174/1567205013666160502122933 CrossRefPubMedGoogle Scholar
  25. Liu-Seifert H, Siemers E, Price K, Han B, Selzler KJ, Henley D, Sundell K, Aisen P, Cummings J, Raskin J, Mohs R (2015) Alzheimer’s disease neuroimaging initiative. cognitive impairment precedes and predicts functional impairment in mild Alzheimer’s disease. J Alzheimers Dis 47:205–214CrossRefPubMedPubMedCentralGoogle Scholar
  26. Martin BS, Corbin JG, Huntsman MM (2014) Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala. J Neurophysiol 112(4):890–902.  https://doi.org/10.1152/jn.00597.2013 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Martínez-Cué C, Martínez P, Rueda N, Vidal R, García S, Vidal V, Corrales A, Montero JA, Pazos Á, Flórez J, Gasser R, Thomas AW, Honer M, Knoflach F, Trejo JL, Wettstein JG, Hernández MC (2013) Reducing GABAA α5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of down syndrome. J Neurosci 33(9):3953–3966.  https://doi.org/10.1523/JNEUROSCI.1203-12.2013 CrossRefPubMedGoogle Scholar
  28. Matsumoto K, Puia G, Dong E, Pinna G (2007) GABAA receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders. Stress 10(1):3–12.  https://doi.org/10.1080/10253890701200997 CrossRefPubMedGoogle Scholar
  29. Mendes-Silva AP, Pereira KS, Tolentino-Araujo GT, Nicolau Ede S, Silva-Ferreira CM, Teixeira AL, Diniz BS (2016) Shared biologic pathways between Alzheimer disease and major depression: a systematic review of microRNA expression studies. Am J Geriatr Psychiatry 24(10):903–912.  https://doi.org/10.1016/j.jagp.2016.07.017 CrossRefPubMedGoogle Scholar
  30. Mirza NR, Larsen JS, Mathiasen C, Jacobsen TA, Munro G, Erichsen HK, Nielsen AN, Troelsen KB, Nielsen EO, Ahring PK (2008) NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a unique subtype-selective GABAA receptor positive allosteric modulator: in vitro actions, pharmacokinetic properties and in vivo anxiolytic efficacy. J Pharmacol Exp Ther 327(3):954–968.  https://doi.org/10.1124/jpet.108.138859 CrossRefPubMedGoogle Scholar
  31. Möhler H (2009) Role of GABAA receptors in cognition. Biochem Soc Trans 37(6):1328–1333.  https://doi.org/10.1042/BST0371328 CrossRefPubMedGoogle Scholar
  32. Moraros J, Nwankwo C, Patten SB, Mousseau DD (2017) The association of antidepressant drug usage with cognitive impairment or dementia, including Alzheimer disease: a systematic review and meta-analysis. Depress Anxiety 34(3):217–226.  https://doi.org/10.1002/da.22584 CrossRefPubMedGoogle Scholar
  33. Mourao RJ, Mansur G, Malloy-Diniz LF, Castro Costa E, Diniz BS (2016) Depressive symptoms increase the risk of progression to dementia in subjects with mild cognitive impairment: systematic review and meta-analysis. Int J Geriatr Psychiatry 31:905–911CrossRefPubMedGoogle Scholar
  34. Nishimura H, Ida Y, Tsuda A, Tanaka M (1989) Opposite effects of diazepam and beta-CCE on immobility and straw-climbing behavior of rats in a modified forced-swim test. Pharmacol Biochem Behav 33(1):227–231.  https://doi.org/10.1016/0091-3057(89)90454-1 CrossRefPubMedGoogle Scholar
  35. Olsen RW, Sieghart W (2008) International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(a) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev 60(3):243–260.  https://doi.org/10.1124/pr.108.00505 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Polc P, Bonetti EP, Schaffner R, Haefely W (1982) A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilizers, β-carbolines, and phenobarbitone. Naunyn Schmiedeberg's Arch Pharmacol 321(4):260–264.  https://doi.org/10.1007/BF00498510 CrossRefGoogle Scholar
  37. Popik P, Kos T, Sowa-Ku_cma M, Nowak G (2008) Lack of persistent effects of ketamine in rodent models of depression. Psychopharmacology 198(3):421–430.  https://doi.org/10.1007/s00213-008-1158-z CrossRefPubMedGoogle Scholar
  38. Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336PubMedGoogle Scholar
  39. Porsteinsson AP, Antonsdottir IM (2017) An update on the advancements in the treatment of agitation in Alzheimer’s disease. Expert Opin Pharmacother 18(6):611–620.  https://doi.org/10.1080/14656566.2017.1307340 CrossRefPubMedGoogle Scholar
  40. Prenosil GA, Schneider Gasser EM, Rudolph U, Keist R, Fritschy JM, Vogt KE (2006) Specific subtypes of GABAA receptors mediate phasic and tonic forms of inhibition in hippocampal pyramidal neurons. J Neurophysiol 96(2):846–857.  https://doi.org/10.1152/jn.01199.2005 CrossRefPubMedGoogle Scholar
  41. Quirk K, Blurton P, Fletcher S, Leeson P, Tang F, Mellilo D, Ragan CI, McKernan RM (1996) [3H]L-655,708, a novel ligand selective for the benzodiazepine site of GABAA receptors which contain the alpha 5 subunit. Neuropharmacology 35(9-10):1331–1335.  https://doi.org/10.1016/S0028-3908(96)00061-5 CrossRefPubMedGoogle Scholar
  42. Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, Guimaraes A, Yue M, Lewis J, Carlson G, Hutton M, Ashe KH (2005) Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 25(46):10637–10647.  https://doi.org/10.1523/JNEUROSCI.3279-05.2005 CrossRefPubMedGoogle Scholar
  43. Rudolph U, Möhler H (2014) GABAA receptor subtypes: therapeutic potential in down syndrome, affective disorders, schizophrenia, and autism. Annu Rev Pharmacol Toxicol 54(1):483–507.  https://doi.org/10.1146/annurev-pharmtox-011613-135947 CrossRefPubMedGoogle Scholar
  44. Savić MM, Clayton T, Furtmüller R, Gavrilović I, Samardzić J, Savić S, Huck S, Sieghart W, Cook JM (2008a) PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(a) receptors containing alpha5 subunits, improves passive, but not active, avoidance learning in rats. Brain Res 1208:150–159.  https://doi.org/10.1016/j.brainres.2008.02.020 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Savić MM, Huang S, Furtmüller R, Clayton T, Huck S, Obradović DI, Ugresić ND, Sieghart W, Bokonjić DR, Cook JM (2008b) Are GABAA receptors containing alpha5 subunits contributing to the sedative properties of benzodiazepine site agonists? Neuropsychopharmacology 33(2):332–339.  https://doi.org/10.1038/sj.npp.1301403 CrossRefPubMedGoogle Scholar
  46. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement 7(3):280–292.  https://doi.org/10.1016/j.jalz.2011.03.003 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacologia 85(3):367–370.  https://doi.org/10.1007/BF00428203 CrossRefGoogle Scholar
  48. Sur C, Fresu L, Howell O, McKernan RM, Atack JR (1999) Autoradiographic localization of alpha5 subunit-containing GABAA receptors in rat brain. Brain Res 822(1-2):265–270.  https://doi.org/10.1016/S0006-8993(99)01152-X CrossRefPubMedGoogle Scholar
  49. Terum TM, Andersen JR, Rongve A, Aarsland D, Svendsboe EJ, Testad I (2017) The relationship of specific items on the Neuropsychiatric Inventory to caregiver burden in dementia: a systematic review. Int J Geriatr Psychiatry 32(7):703–717.  https://doi.org/10.1002/gps.4704 CrossRefPubMedGoogle Scholar
  50. Thiébot MH, Soubrié P, Sanger D (1988) Anxiogenic properties of beta-CCE and FG 7142: a review of promises and pitfalls. Psychopharmacology 94:452–463CrossRefPubMedGoogle Scholar
  51. Towers SK, Gloveli T, Traub RD, Driver JE, Engel D, Fradley R, Rosahl TW, Maubach K, Buhl EH, Whittington MA (2004) Alpha 5 subunit-containing GABAA receptors affect the dynamic range of mouse hippocampal kainate-induced gamma frequency oscillations in vitro. J Physiol 559(3):721–728.  https://doi.org/10.1113/jphysiol.2004.071191 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Trullas R, Skolnick P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185(1):1–10.  https://doi.org/10.1016/0014-2999(90)90204-J CrossRefPubMedGoogle Scholar
  53. Van der Jeugd A, Blum D, Raison S, Eddarkaoui S, Buee L, D'Hooge R (2013) Observations in THY-Tau22 mice that resemble behavioral and psychological signs and symptoms of dementia. Behav Brain Res 242:34–39.  https://doi.org/10.1016/j.bbr.2012.12.008 CrossRefPubMedGoogle Scholar
  54. Varagic Z, Wimmer L, Schnürch M, Mihovilovic MD, Huang S, Rallapalli S, Cook JM, Mirheydari P, Ecker GF, Sieghart W, Ernst M (2013) Identification of novel positive allosteric modulators and null modulators at the GABAA receptor α+β- interface. Br J Pharmacol 169(2):371–383.  https://doi.org/10.1111/bph.12151 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Zanos P, Nelson ME, Highland JN, Krimmel SR, Georgiou P, Gould TD, Thompson SM (2017) A Negative allosteric modulator for α5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice. eNeuro 4(1):0285–16.2017.  https://doi.org/10.1523/ENEURO.0285-16.2017 CrossRefGoogle Scholar
  56. Zarnowska ED, Keist R, Rudolph U, Pearce RA (2009) GABAA receptor alpha5 subunits contribute to GABAA, slow synaptic inhibition in mouse hippocampus. J Neurophysiol 101(3):1179–1191.  https://doi.org/10.1152/jn.91203.2008 CrossRefPubMedGoogle Scholar
  57. Zhao QF, Tan L, Wang HF, Jiang T, Tan MS, Tan L, Xu W, Li JQ, Wang J, Lai TJ, Yu JT (2016) The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: Systematic review and meta-analysis. J Affect Disord 190:264–271.  https://doi.org/10.1016/j.jad.2015.09.069 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Nina Z. Xu
    • 1
  • Margot Ernst
    • 2
  • Marco Treven
    • 2
  • Rok Cerne
    • 1
  • Mark Wakulchik
    • 1
  • Xia Li
    • 1
  • Timothy M. Jones
    • 1
  • Scott D. Gleason
    • 1
  • Denise Morrow
    • 1
  • Jeffrey M. Schkeryantz
    • 1
  • Md. Toufiqur Rahman
    • 3
  • Guanguan Li
    • 3
  • Michael M. Poe
    • 3
  • James M. Cook
    • 3
  • Jeffrey M. Witkin
    • 1
  1. 1.The Lilly Research LabsEli Lilly and CompanyIndianapolisUSA
  2. 2.Department of Molecular Neurosciences Center for Brain ResearchMedical University of ViennaViennaAustria
  3. 3.Department of Chemistry and BiochemistryUniversity of Wisconsin MilwaukeeMilwaukeeUSA

Personalised recommendations