Skip to main content
SpringerLink
Log in

Enhancing the Utility of Preclinical Research in Neuropsychiatry Drug Development

  • Protocol
  • First Online:
Psychiatric Disorders

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2011))

Abstract

Most large pharmaceutical companies have downscaled or closed their clinical neuroscience research programs in response to the low clinical success rate for drugs that showed tremendous promise in animal experiments intended to model psychiatric pathophysiology. These failures have raised serious concerns about the role of preclinical research in the identification and evaluation of new pharmacotherapies for psychiatry. In the absence of a comprehensive understanding of the neurobiology of psychiatric disorders, the task of developing “animal models” seems elusive. The purpose of this review is to highlight emerging strategies to enhance the utility of preclinical research in the drug development process. We address this issue by reviewing how advances in neuroscience, coupled with new conceptual approaches, have recently revolutionized the way we can diagnose and treat common psychiatric conditions. We discuss the implications of these new tools for modeling psychiatric conditions in animals and advocate for the use of systematic reviews of preclinical work as a prerequisite for conducting psychiatric clinical trials. We believe that work in animals is essential for elucidating human psychopathology and that improving the predictive validity of animal models is necessary for developing more effective interventions for mental illness.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. O’Brien PL, Thomas CP, Hodgkin D, Levit KR, Mark TL (2014) The diminished pipeline for medications to treat mental health and substance use disorders. Psychiatr Serv 65:1433–1438

    PubMed  PubMed Central  Google Scholar 

  2. Miller G (2010) Is pharma running out of brainy ideas? Science 329:502–504

    CAS  PubMed  Google Scholar 

  3. Hyman SE (2010) The diagnosis of mental disorders: the problem of reification. Annu Rev Clin Psychol 6:155–179

    PubMed  Google Scholar 

  4. Kaffman A, Krystal JH (2012) New frontiers in animal research of psychiatric illness. Methods Mol Biol 829:3–30

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, Fetcho RN, Zebley B, Oathes DJ, Etkin A, Schatzberg AF, Sudheimer K, Keller J, Mayberg HS, Gunning FM, Alexopoulos GS, Fox MD, Pascual-Leone A, Voss HU, Casey BJ, Dubin MJ, Liston C (2017) Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med 23:28–38

    CAS  PubMed  Google Scholar 

  6. Griebel G, Holmes A (2013) 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 12:667–687

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245

    CAS  PubMed  Google Scholar 

  9. Greek R, Menache A (2013) Systematic reviews of animal models: methodology versus epistemology. Int J Med Sci 10:206–221

    PubMed  PubMed Central  Google Scholar 

  10. Willner P (1984) The validity of animal models of depression. Psychopharmacology 83:1–16

    CAS  Google Scholar 

  11. Ban TA (2006) The role of serendipity in drug discovery. Dialogues Clin Neurosci 8:335–344

    PubMed  PubMed Central  Google Scholar 

  12. Wong EHF, Yocca F, Smith MA, Lee CM (2010) Challenges and opportunities for drug discovery in psychiatric disorders: the drug hunters’ perspective. Int J Neuropsychopharmacol 13:1269–1284

    PubMed  Google Scholar 

  13. Spierling SR, Zorrilla EP (2017) Don’t stress about CRF: assessing the translational failures of CRF1 antagonists. Psychopharmacology 234:1467–1481

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Spencer S, Kalivas PW (2017) Glutamate transport: a new bench to bedside mechanism for treating drug abuse. Int J Neuropsychopharmacol 20:797–812

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P, Visootsak J, Brinkman M, Rerat K, Koumaras B, Zhu L, Barth GM, Jaecklin T, Apostol G, von Raison F (2016) Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med 8:321ra325

    Google Scholar 

  16. Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, Jacob Filho W, Lent R, Herculano-Houzel S (2009) Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol 513:532–541

    PubMed  Google Scholar 

  17. van Gerven M (2017) Computational foundations of natural intelligence. Front Comput Neurosci 11:112

    PubMed  PubMed Central  Google Scholar 

  18. Hyman SE (2008) A glimmer of light for neuropsychiatric disorders. Nature 455:890–893

    CAS  PubMed  Google Scholar 

  19. Regier DA, Narrow WE, Clarke DE, Kraemer HC, Kuramoto SJ, Kuhl EA, Kupfer DJ (2013) DSM-5 field trials in the United States and Canada, Part II: test-retest reliability of selected categorical diagnoses. Am J Psychiatry 170:59–70

    PubMed  Google Scholar 

  20. Helzer JE, Clayton PJ, Pambakian R, Reich T, Woodruff RA Jr, Reveley MA (1977) Reliability of psychiatric diagnosis. II. The test/retest reliability of diagnostic classification. Arch Gen Psychiatry 34:136–141

    CAS  PubMed  Google Scholar 

  21. Helzer JE, Robins LN, Taibleson M, Woodruff RA Jr, Reich T, Wish ED (1977) Reliability of psychiatric diagnosis. I. A methodological review. Arch Gen Psychiatry 34:129–133

    CAS  PubMed  Google Scholar 

  22. Pies R (2007) How “objective” are psychiatric diagnoses?: (guess again). Psychiatry (Edgmont) 4:18–22

    Google Scholar 

  23. Martinez G, Vernooij RW, Fuentes Padilla P, Zamora J, Bonfill Cosp X, Flicker L (2017) 18F PET with florbetapir for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev (11):CD012216

    Google Scholar 

  24. Villemagne VL, Dore V, Burnham SC, Masters CL, Rowe CC (2018) Imaging tau and amyloid-beta proteinopathies in Alzheimer disease and other conditions. Nat Rev Neurol 14(4):225–236

    CAS  PubMed  Google Scholar 

  25. Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, Bloomfield MA, Bonoldi I, Kalk N, Turkheimer F, McGuire P, de Paola V, Howes OD (2016) Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [(11)C]PBR28 PET brain imaging study. Am J Psychiatry 173:44–52

    PubMed  Google Scholar 

  26. Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, Suridjan I, Kennedy JL, Rekkas PV, Houle S, Meyer JH (2015) Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiat 72:268–275

    Google Scholar 

  27. Klunk WE, Engler H, Nordberg A, Wang YM, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Langstrom B (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55:306–319

    CAS  PubMed  Google Scholar 

  28. Mathis CA, Bacskai BJ, Kajdasz ST, McLellan ME, Frosch MP, Hyman BT, Holt DP, Wang YM, Huang GF, Debnath ML, Klunk WE (2002) A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem Lett 12:295–298

    CAS  PubMed  Google Scholar 

  29. Bacskai BJ, Hickey GA, Skoch J, Kajdasz ST, Wang Y, Huang GF, Mathis CA, Klunk WE, Hyman BT (2003) Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A 100:12462–12467

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Karlstetter M, Nothdurfter C, Aslanidis A, Moeller K, Horn F, Scholz R, Neumann H, Weber BH, Rupprecht R, Langmann T (2014) Translocator protein (18 kDa) (TSPO) is expressed in reactive retinal microglia and modulates microglial inflammation and phagocytosis. J Neuroinflammation 11:3

    PubMed  PubMed Central  Google Scholar 

  31. Banati RB (2002) Visualising microglial activation in vivo. Glia 40:206–217

    PubMed  Google Scholar 

  32. Johnson FK, Kaffman A (2017) Early life stress perturbs the function of microglia in the developing rodent brain: new insights and future challenges. Brain Behav Immun 69:18–27

    PubMed  PubMed Central  Google Scholar 

  33. Sehlin D, Fang XTT, Cato L, Antoni G, Lannfelt L, Syvanen S (2016) Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer’s disease. Nat Commun 7:10759

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mulholland PJ, Chandler LJ, Kalivas PW (2016) Signals from the fourth dimension regulate drug relapse. Trends Neurosci 39:472–485

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Jonckers E, Shah D, Hamaide J, Verhoye M, Van der Linden A (2015) The power of using functional fMRI on small rodents to study brain pharmacology and disease. Front Pharmacol 6:231

    PubMed  PubMed Central  Google Scholar 

  36. Wu D, Zhang J (2016) Recent progress in magnetic resonance imaging of the embryonic and neonatal mouse brain. Front Neuroanat 10:18

    PubMed  PubMed Central  Google Scholar 

  37. Johnson FK, Delpech JC, Thompson GJ, Wei L, Hao J, Herman P, Hyder F, Kaffman A (2018) Amygdala hyper-connectivity in a mouse model of unpredictable early life stress. Transl Psychiatry 8:49

    PubMed  PubMed Central  Google Scholar 

  38. van der Werff SJ, Pannekoek JN, Veer IM, van Tol MJ, Aleman A, Veltman DJ, Zitman FG, Rombouts SA, Elzinga BM, van der Wee NJ (2013) Resting-state functional connectivity in adults with childhood emotional maltreatment. Psychol Med 43:1825–1836

    PubMed  Google Scholar 

  39. Birn RM, Patriat R, Phillips ML, Germain A, Herringa RJ (2014) Childhood maltreatment and combat posttraumatic stress differentially predict fear-related fronto-subcortical connectivity. Depress Anxiety 31:880–892

    PubMed  PubMed Central  Google Scholar 

  40. Herringa RJ, Phillips ML, Fournier JC, Kronhaus DM, Germain A (2013) Childhood and adult trauma both correlate with dorsal anterior cingulate activation to threat in combat veterans. Psychol Med 43:1533–1542

    CAS  PubMed  Google Scholar 

  41. Wang L, Dai Z, Peng H, Tan L, Ding Y, He Z, Zhang Y, Xia M, Li Z, Li W, Cai Y, Lu S, Liao M, Zhang L, Wu W, He Y, Li L (2014) Overlapping and segregated resting-state functional connectivity in patients with major depressive disorder with and without childhood neglect. Hum Brain Mapp 35:1154–1166

    PubMed  Google Scholar 

  42. Cisler JM, James GA, Tripathi S, Mletzko T, Heim C, Hu XP, Mayberg HS, Nemeroff CB, Kilts CD (2013) Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress. Psychol Med 43:507–518

    CAS  PubMed  Google Scholar 

  43. Dean AC, Kohno M, Hellemann G, London ED (2014) Childhood maltreatment and amygdala connectivity in methamphetamine dependence: a pilot study. Brain Behav 4:867–876

    PubMed  PubMed Central  Google Scholar 

  44. Philip NS, Sweet LH, Tyrka AR, Price LH, Bloom RF, Carpenter LL (2013) Decreased default network connectivity is associated with early life stress in medication-free healthy adults. Eur Neuropsychopharmacol 23:24–32

    CAS  PubMed  Google Scholar 

  45. Wiegert JS, Mahn M, Prigge M, Printz Y, Yizhar O (2017) Silencing neurons: tools, applications, and experimental constraints. Neuron 95:504–529

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Jiang J, Cui H, Rahmouni K (2017) Optogenetics and pharmacogenetics: principles and applications. Am J Physiol Regul Integr Comp Physiol 313:R633–R645

    PubMed  PubMed Central  Google Scholar 

  47. Galvan A, Stauffer WR, Acker L, El-Shamayleh Y, Inoue KI, Ohayon S, Schmid MC (2017) Nonhuman primate optogenetics: recent advances and future directions. J Neurosci 37:10894–10903

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Anthony TE, Dee N, Bernard A, Lerchner W, Heintz N, Anderson DJ (2014) Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 156:522–536

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Pena CJ, Kronman HG, Walker DM, Cates HM, Bagot RC, Purushothaman I, Issler O, Loh YE, Leong T, Kiraly DD, Goodman E, Neve RL, Shen L, Nestler EJ (2017) Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science 356:1185–1188

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Varghese M, Keshav N, Jacot-Descombes S, Warda T, Wicinski B, Dickstein DL, Harony-Nicolas H, De Rubeis S, Drapeau E, Buxbaum JD, Hof PR (2017) Autism spectrum disorder: neuropathology and animal models. Acta Neuropathol 134:537–566

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Monteiro P, Feng G (2017) SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat Rev Neurosci 18:147–157

    CAS  PubMed  Google Scholar 

  52. Wapinski OL, Vierbuchen T, Qu K, Lee QY, Chanda S, Fuentes DR, Giresi PG, Ng YH, Marro S, Neff NF, Drechsel D, Martynoga B, Castro DS, Webb AE, Sudhof TC, Brunet A, Guillemot F, Chang HY, Wernig M (2013) Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 155:621–635

    CAS  PubMed  Google Scholar 

  53. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    CAS  PubMed  Google Scholar 

  54. Parr CJC, Yamanaka S, Saito H (2017) An update on stem cell biology and engineering for brain development. Mol Psychiatry 22:808–819

    CAS  PubMed  Google Scholar 

  55. Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, Beaumont KG, Kim HJ, Topol A, Ladran I, Abdelrahim M, Matikainen-Ankney B, Chao SH, Mrksich M, Rakic P, Fang G, Zhang B, Yates JR III, Gage FH (2015) Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 20:361–368

    CAS  PubMed  Google Scholar 

  56. Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, Nehme R, van der Ven K, Hsu J, Wolf P, Fleishman M, O’Dushlaine C, Rose S, Chambert K, Lau FH, Ahfeldt T, Rueckert EH, Sheridan SD, Fass DM, Nemesh J, Mullen TE, Daheron L, McCarroll S, Sklar P, Perlis RH, Haggarty SJ (2015) Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry 20:703–717

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, Goldstein LS (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482:216–220

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Yi F, Danko T, Botelho SC, Patzke C, Pak C, Wernig M, Sudhof TC (2016) Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science 352:aaf2669

    PubMed  PubMed Central  Google Scholar 

  59. Testolin A, Stoianov I, Zorzi M (2017) Letter perception emerges from unsupervised deep learning and recycling of natural image features. Nat Hum Behav 1:843

    Google Scholar 

  60. Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, Sanislow C, Wang P (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 167:748–751

    PubMed  Google Scholar 

  61. Delgado MR, Nearing KI, Ledoux JE, Phelps EA (2008) Neural circuitry underlying the regulation of conditioned fear and its relation to extinction. Neuron 59:829–838

    CAS  PubMed  PubMed Central  Google Scholar 

  62. LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184

    CAS  PubMed  Google Scholar 

  63. Widiger TA, Clark LA (2000) Toward DSM-V and the classification of psychopathology. Psychol Bull 126:946–963

    CAS  PubMed  Google Scholar 

  64. Gordon J (2018) The future of RDoC. National Institute of Mental Health, Bethesda, MD

    Google Scholar 

  65. Lohr KN (2004) Rating the strength of scientific evidence: relevance for quality improvement programs. Int J Qual Health Care 16:9–18

    PubMed  Google Scholar 

  66. Sandercock P, Roberts I (2002) Systematic reviews of animal experiments. Lancet 360:586

    PubMed  Google Scholar 

  67. Horn J, Limburg M (2001) Calcium antagonists for ischemic stroke: a systematic review. Stroke 32:570–576

    CAS  PubMed  Google Scholar 

  68. Horn J, de Haan RJ, Vermeulen M, Luiten PG, Limburg M (2001) Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke 32:2433–2438

    CAS  PubMed  Google Scholar 

  69. Hooijmans CR, Ritskes-Hoitinga M (2013) Progress in using systematic reviews of animal studies to improve translational research. PLoS Med 10:e1001482

    CAS  PubMed  PubMed Central  Google Scholar 

  70. van der Worp HB, Macleod MR, Kollmar R, European Stroke Research Network for, H (2010) Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? J Cereb Blood Flow Metab 30:1079–1093

    PubMed  PubMed Central  Google Scholar 

  71. Khan MS, Boileau I, Kolla N, Mizrahi R (2018) A systematic review of the role of the nociceptin receptor system in stress, cognition, and reward: relevance to schizophrenia. Transl Psychiatry 8:38

    PubMed  PubMed Central  Google Scholar 

  72. Kaffman A, Meaney MJ (2007) Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights. J Child Psychol Psychiatry 48:224–244

    PubMed  Google Scholar 

  73. Mignot EJ (2014) History of narcolepsy at Stanford University. Immunol Res 58:315–339

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Scammell TE (2003) The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 53:154–166

    PubMed  Google Scholar 

  75. Winrow CJ, Renger JJ (2014) Discovery and development of orexin receptor antagonists as therapeutics for insomnia. Br J Pharmacol 171:283–293

    CAS  PubMed  Google Scholar 

  76. Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF (2007) Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397–410

    CAS  PubMed  Google Scholar 

  77. Arnsten AF, Wang M (2016) Targeting prefrontal cortical systems for drug development: potential therapies for cognitive disorders. Annu Rev Pharmacol Toxicol 56:339–360

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Connor DF, Arnsten AFT, Pearson GS, Greco GF (2014) Guanfacine extended release for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. Expert Opin Pharmacol 15:1601–1610

    CAS  Google Scholar 

  79. von Budingen HC, Hauser SL, Ouallet JC, Tanuma N, Menge T, Genain CP (2004) Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences disease phenotype and antibody effector functions in autoimmune demyelination. Eur J Immunol 34:2072–2083

    Google Scholar 

  80. von Budingen HC, Tanuma N, Villoslada P, Ouallet JC, Hauser SL, Genain CP (2001) Immune responses against the myelin/oligodendrocyte glycoprotein in experimental autoimmune demyelination. J Clin Immunol 21:155–170

    Google Scholar 

  81. von Budingen HC, Hauser SL, Fuhrmann A, Nabavi CB, Lee JI, Genain CP (2002) Molecular characterization of antibody specificities against myelin/oligodendrocyte glycoprotein in autoimmune demyelination. Proc Natl Acad Sci U S A 99:8207–8212

    Google Scholar 

  82. Dolgin E (2016) Therapies: progressive steps. Nature 540:S7–S9

    CAS  PubMed  Google Scholar 

  83. Gelfand JM, Cree BAC, Hauser SL (2017) Ocrelizumab and other CD20+ B-cell-depleting therapies in multiple sclerosis. Neurotherapeutics 14(4):835–841

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Sanders J, Nemeroff C (2016) The CRF system as a therapeutic target for neuropsychiatric disorders. Trends Pharmacol Sci 37:1045–1054

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557

    CAS  PubMed  Google Scholar 

  86. Henckens MJ, Deussing JM, Chen A (2016) Region-specific roles of the corticotropin-releasing factor-urocortin system in stress. Nat Rev Neurosci 17:636–651

    CAS  PubMed  Google Scholar 

  87. Gray TS (1993) Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral responses to stress. Ann N Y Acad Sci 697:53–60

    CAS  PubMed  Google Scholar 

  88. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1–12

    CAS  PubMed  Google Scholar 

  89. Seckl JR (2008) Glucocorticoids, developmental ‘programming’ and the risk of affective dysfunction. Prog Brain Res 167:17–34

    CAS  PubMed  Google Scholar 

  90. Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med 353:1711–1723

    CAS  PubMed  Google Scholar 

  91. Ramamoorthy S, Cidlowski JA (2016) Corticosteroids: mechanisms of action in health and disease. Rheum Dis Clin N Am 42:15–31, vii

    Google Scholar 

  92. De Francesco PN, Valdivia S, Cabral A, Reynaldo M, Raingo J, Sakata I, Osborne-Lawrence S, Zigman JM, Perello M (2015) Neuroanatomical and functional characterization of CRF neurons of the amygdala using a novel transgenic mouse model. Neuroscience 289:153–165

    PubMed  PubMed Central  Google Scholar 

  93. Bolton JL, Molet J, Regev L, Chen Y, Rismanchi N, Haddad E, Yang DZ, Obenaus A, Baram TZ (2018) Anhedonia following early-life adversity involves aberrant interaction of reward and anxiety circuits and is reversed by partial silencing of amygdala corticotropin-releasing hormone gene. Biol Psychiatry 83:137–147

    CAS  PubMed  Google Scholar 

  94. Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, Phillips PE (2012) Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature 490:402–406

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Chen Y, Bender RA, Frotscher M, Baram TZ (2001) Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J Neurosci 21:7171–7181

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Ivy AS, Rex CS, Chen Y, Dube C, Maras PM, Grigoriadis DE, Gall CM, Lynch G, Baram TZ (2010) Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J Neurosci 30:13005–13015

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Chen Y, Baram TZ (2016) Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology 41:197–206

    PubMed  Google Scholar 

  98. Ivy AS, Brunson KL, Sandman C, Baram TZ (2008) Dysfunctional nurturing behavior in rat dams with limited access to nesting material: a clinically relevant model for early-life stress. Neuroscience 154:1132–1142

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Kolber BJ, Boyle MP, Wieczorek L, Kelley CL, Onwuzurike CC, Nettles SA, Vogt SK, Muglia LJ (2010) Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice. J Neurosci 30:2571–2581

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Brunson KL, Grigoriadis DE, Lorang MT, Baram TZ (2002) Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain. Exp Neurol 176:75–86

    CAS  PubMed  Google Scholar 

  101. Wang XD, Su YA, Wagner KV, Avrabos C, Scharf SH, Hartmann J, Wolf M, Liebl C, Kuhne C, Wurst W, Holsboer F, Eder M, Deussing JM, Muller MB, Schmidt MV (2013) Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. Nat Neurosci 16:706–713

    CAS  PubMed  Google Scholar 

  102. Wang XD, Labermaier C, Holsboer F, Wurst W, Deussing JM, Muller MB, Schmidt MV (2012) Early-life stress-induced anxiety-related behavior in adult mice partially requires forebrain corticotropin-releasing hormone receptor 1. Eur J Neurosci 36:2360–2367

    PubMed  Google Scholar 

  103. Bolton JL, Molet J, Ivy A, Baram TZ (2017) New insights into early-life stress and behavioral outcomes. Curr Opin Behav Sci 14:133–139

    PubMed  PubMed Central  Google Scholar 

  104. Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM, Dedic N, Schumacher M, von Wolff G, Avrabos C, Touma C, Engblom D, Schutz G, Nave KA, Eder M, Wotjak CT, Sillaber I, Holsboer F, Wurst W, Deussing JM (2011) Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333:1903–1907

    CAS  PubMed  Google Scholar 

  105. Piazza PV, Deroche-Gamonet V (2013) A multistep general theory of transition to addiction. Psychopharmacology 229:387–413

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Namba MD, Tomek SE, Olive MF, Beckmann JS, Gipson CD (2018) The winding road to relapse: forging a new understanding of cue-induced reinstatement models and their associated neural mechanisms. Front Behav Neurosci 12:17

    PubMed  PubMed Central  Google Scholar 

  107. Epstein DH, Preston KL, Stewart J, Shaham Y (2006) Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology 189:1–16

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Kasanetz F, Deroche-Gamonet V, Berson N, Balado E, Lafourcade M, Manzoni O, Piazza PV (2010) Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science 328:1709–1712

    CAS  PubMed  Google Scholar 

  109. Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868

    CAS  PubMed  Google Scholar 

  110. Bourke CH, Glasper ER, Neigh GN (2014) SSRI or CRF antagonism partially ameliorate depressive-like behavior after adolescent social defeat. Behav Brain Res 270:295–299

    CAS  PubMed  Google Scholar 

  111. Ayala AR, Pushkas J, Higley JD, Ronsaville D, Gold PW, Chrousos GP, Pacak K, Calis KA, Gerald M, Lindell S, Rice KC, Cizza G (2004) Behavioral, adrenal, and sympathetic responses to long-term administration of an oral corticotropin-releasing hormone receptor antagonist in a primate stress paradigm. J Clin Endocrinol Metab 89:5729–5737

    CAS  PubMed  Google Scholar 

  112. Habib KE, Weld KP, Rice KC, Pushkas J, Champoux M, Listwak S, Webster EL, Atkinson AJ, Schulkin J, Contoreggi C, Chrousos GP, McCann SM, Suomi SJ, Higley JD, Gold PW (2000) Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc Natl Acad Sci U S A 97:6079–6084

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Walker D, Yang Y, Ratti E, Corsi M, Trist D, Davis M (2009) Differential effects of the CRF-R1 antagonist GSK876008 on fear-potentiated, light- and CRF-enhanced startle suggest preferential involvement in sustained vs phasic threat responses. Neuropsychopharmacology 34:1533–1542

    CAS  PubMed  Google Scholar 

  114. Garcia-Garcia AL, Newman-Tancredi A, Leonardo ED (2014) 5-HT(1A) [corrected] receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function. Psychopharmacology 231:623–636

    CAS  PubMed  Google Scholar 

  115. Gross C, Hen R (2004) The developmental origins of anxiety. Nat Rev Neurosci 5:545–552

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by NARSAD Independent Investigator Award 2016, NIMH grant R01 MH-100078, and the Clinical Neuroscience Division of the VA National Center for PTSD.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Arie Kaffman, Jordon D. White, Lan Wei, Frances K. Johnson & John H. Krystal

Authors
  1. Arie Kaffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jordon D. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lan Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frances K. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John H. Krystal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arie Kaffman .

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

    Firas H. Kobeissy

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Kaffman, A., White, J.D., Wei, L., Johnson, F.K., Krystal, J.H. (2019). Enhancing the Utility of Preclinical Research in Neuropsychiatry Drug Development. In: Kobeissy, F. (eds) Psychiatric Disorders. Methods in Molecular Biology, vol 2011. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9554-7_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9554-7_1

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9553-0

  • Online ISBN: 978-1-4939-9554-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation