Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A preliminary study of the effects of an antimuscarinic agent on anxious behaviors and white matter microarchitecture in nonhuman primates

Neuropsychopharmacology volume 49, pages 405–413 (2024)Cite this article

Subjects

Abstract

Myelination subserves efficient neuronal communication, and alterations in white matter (WM) microstructure have been implicated in numerous psychiatric disorders, including pathological anxiety. Recent work in rodents suggests that muscarinic antagonists may enhance myelination with behavioral benefits; however, the neural and behavioral effects of muscarinic antagonists have yet to be explored in non-human primates (NHP). Here, as a potentially translatable therapeutic strategy for human pathological anxiety, we present data from a first-in-primate study exploring the effects of the muscarinic receptor antagonist solifenacin on anxious behaviors and WM microstructure. 12 preadolescent rhesus macaques (6 vehicle control, 6 experimental; 8F, 4M) were included in a pre-test/post-test between-group study design. The experimental group received solifenacin succinate for ~60 days. Subjects underwent pre- and post-assessments of: 1) anxious temperament (AT)-related behaviors in the potentially threatening no-eye-contact (NEC) paradigm (30-min); and 2) WM and regional brain metabolism imaging metrics, including diffusion tensor imaging (DTI), quantitative relaxometry (QR), and FDG-PET. In relation to anxiety-related behaviors expressed during the NEC, significant Group (vehicle control vs. solifenacin) by Session (pre vs. post) interactions were found for freezing, cooing, and locomotion. Compared to vehicle controls, solifenacin-treated subjects exhibited effects consistent with reduced anxiety, specifically decreased freezing duration, increased locomotion duration, and increased cooing frequency. Furthermore, the Group-by-Session-by-Sex interaction indicated that these effects occurred predominantly in the males. Exploratory whole-brain voxelwise analyses of post-minus-pre differences in DTI, QR, and FDG-PET metrics revealed some solifenacin-related changes in WM microstructure and brain metabolism. These findings in NHPs support the further investigation of the utility of antimuscarinic agents in targeting WM microstructure as a means to treat pathological anxiety.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Schematic of the experimental design and timeline.
Fig. 2: Group-by-Session-by-Sex interaction in relation to freezing behavior in the 30-min NEC.
Fig. 3: Group-by-Session-by-Sex interaction in relation to cooing behavior in the 30-min NEC.
Fig. 4: Group-by-session interaction in relation to WM metrics (qR1 and FA) in voxelwise analyses.
Fig. 5: Group-by-Session interaction in relation to FDG in voxelwise analyses.

Similar content being viewed by others

References

  1. Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J methods Psychiatr Res. 2012;21:169–84.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Konnopka A, König H. Economic burden of anxiety disorders: a systematic review and meta-analysis. Pharmacoeconomics. 2020;38:25–37.

  3. Bandelow B, Michaelis S. Epidemiology of anxiety disorders in the 21st century. Dialogues Clin Neurosci. 2015;17:327–35.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yang X, Fang Y, Chen H, Zhang T, Yin X, Man J, et al. Global, regional and national burden of anxiety disorders from 1990 to 2019: results from the Global Burden of Disease Study 2019. Epidemiol Psych Sci. 2021;30:e36.

    Article  Google Scholar 

  5. Bandelow B, Michaelis S, Wedekind D. Treatment of anxiety disorders. Dialogues Clin Neurosci. 2017;19:93–107.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ginsburg GS, Becker-Haimes EM, Keeton C, Kendall PC, Iyengar S, Sakolsky D, et al. Results from the child/adolescent anxiety multimodal extended long-term study (CAMELS): primary anxiety outcomes. J Am Acad Child Adolesc Psychiatry. 2018;57:471–80.

    Article  PubMed  Google Scholar 

  7. Ginsburg GS, Becker EM, Keeton CP, Sakolsky D, Piacentini J, Albano AM, et al. Naturalistic follow-up of youths treated for pediatric anxiety disorders. JAMA Psychiatry. 2014;71:310–8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Scholten W, Have M ten, Geel C van, Balkom A van, Graaf R de, Batelaan N. Recurrence of anxiety disorders and its predictors in the general population. Psychol Med. 2023;53:1334–42.

  9. Barnea-Goraly N, Menon V, Eckert M, Tamm L, Bammer R, Karchemskiy A, et al. White matter development during childhood and adolescence: a cross-sectional diffusion tensor imaging study. Cereb Cortex. 2005;15:1848–54.

    Article  PubMed  Google Scholar 

  10. Lebel C, Beaulieu C. Longitudinal development of human brain wiring continues from childhood into adulthood. J Neurosci. 2011;31:10937–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Costello EJ, Mustillo S, Erkanli A, Keeler G, Angold A. Prevalence and development of psychiatric disorders in childhood and adolescence. Arch Gen Psychiatry. 2003;60:837–44.

    Article  PubMed  Google Scholar 

  12. Aggarwal N, Williams LE, Tromp DPM, Pine DS, Kalin NH. A dynamic relation between whole-brain white matter microstructural integrity and anxiety symptoms in preadolescent females with pathological anxiety. Transl Psychiatry. 2022;12:57.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tromp DPM, Williams LE, Fox AS, Oler JA, Roseboom PH, Rogers GM, et al. Altered uncinate fasciculus microstructure in childhood anxiety disorders in boys but not girls. Am J Psychiatry. 2019;176:208–16.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Fields RD. Myelin formation and remodeling. Cell. 2014;156:15–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Miron VE, Kuhlmann T, Antel JP. Cells of the oligodendroglial lineage, myelination, and remyelination. Biochim Biophys Acta 2011;1812:184–93.

    Article  CAS  PubMed  Google Scholar 

  16. Friedrich P, Fraenz C, Schlüter C, Ocklenburg S, Mädler B, Güntürkün O, et al. The relationship between axon density, myelination, and fractional anisotropy in the human corpus callosum. Cereb Cortex. 2020;30:2042–56.

    Article  PubMed  Google Scholar 

  17. Roberts TPL, Liu F, Kassner A, Mori S, Guha A. Fiber density index correlates with reduced fractional anisotropy in white matter of patients with glioblastoma. Am J Neuroradiol. 2005;26:2183–6.

    PubMed  PubMed Central  Google Scholar 

  18. Beaulieu C. The basis of anisotropic water diffusion in the nervous system—a technical review. NMR Biomed. 2002;15:435–55.

    Article  PubMed  Google Scholar 

  19. Lazari A, Lipp I. Can MRI measure myelin? systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology. Neuroimage. 2021;230:117744.

    Article  PubMed  Google Scholar 

  20. Song SK, Yoshino J, Le TQ, Lin SJ, Sun SW, Cross AH, et al. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage. 2005;26:132–40.

    Article  PubMed  Google Scholar 

  21. Tromp DPM, Grupe DW, Oathes DJ, McFarlin DR, Hernandez PJ, Kral TRA, et al. Reduced structural connectivity of a major frontolimbic pathway in generalized anxiety disorder. Arch Gen psychiatry. 2012;69:925–34.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Baur V, Hänggi J, Rufer M, Delsignore A, Jäncke L, Herwig U, et al. White matter alterations in social anxiety disorder. J Psychiatr Res. 2011;45:1366–72.

    Article  PubMed  Google Scholar 

  23. Kim MJ, Whalen PJ. The structural integrity of an amygdala-prefrontal pathway predicts trait anxiety. J Neurosci. 2009;29:11614–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liao M, Yang F, Zhang Y, He Z, Su L, Li L. White matter abnormalities in adolescents with generalized anxiety disorder: a diffusion tensor imaging study. BMC Psychiatry. 2014;14:41.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Westlye LT, Bjørnebekk A, Grydeland H, Fjell AM, Walhovd KB. Linking an anxiety-related personality trait to brain white matter microstructure: diffusion tensor imaging and harm avoidance. Arch Gen Psychiatry. 2011;68:369–77.

    Article  PubMed  Google Scholar 

  26. Tromp DPM, Fox AS, Oler JA, Alexander AL, Kalin NH. The relationship between the uncinate fasciculus and anxious temperament is evolutionarily conserved and sexually dimorphic. Biol Psychiatry. 2019;86:890–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Aggarwal N, Moody JF, Dean IDC, Tromp DPM, Kecskemeti SR, Oler JA, et al. Spatiotemporal dynamics of nonhuman primate white matter development during the first year of life. Neuroimage. 2021;231:117825.

    Article  PubMed  Google Scholar 

  28. Dimond D, Rohr CS, Smith RE, Dhollander T, Cho I, Lebel C, et al. Early childhood development of white matter fiber density and morphology. Neuroimage. 2020;210:116552.

    Article  PubMed  Google Scholar 

  29. Scholz J, Klein MC, Behrens TEJ, Johansen-Berg H. Training induces changes in white-matter architecture. Nat Neurosci. 2009;12:1370–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sampaio-Baptista C, Khrapitchev AA, Foxley S, Schlagheck T, Scholz J, Jbabdi S, et al. Motor skill learning induces changes in white matter microstructure and myelination. J Neurosci. 2013;33:19499–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu J, Dupree JL, Gacias M, Frawley R, Sikder T, Naik P, et al. Clemastine enhances myelination in the prefrontal cortex and rescues behavioral changes in socially isolated mice. J Neurosci. 2016;36:957–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Abiraman K, Pol SU, O’Bara MA, Chen GD, Khaku ZM, Wang J, et al. Anti-muscarinic adjunct therapy accelerates functional human oligodendrocyte repair. J Neurosci. 2015;35:3676–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Welliver RR, Polanco JJ, Seidman RA, Sinha AK, O’Bara MA, Khaku ZM, et al. Muscarinic receptor m3r signaling prevents efficient remyelination by human and mouse oligodendrocyte progenitor cells. J Neurosci. 2018;38:6921–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fields RD, Dutta DJ, Belgrad J, Robnett M. Cholinergic signaling in myelination. Glia. 2017;65:687–98.

    Article  PubMed  Google Scholar 

  35. Pan S, Mayoral SR, Choi HS, Chan JR, Kheirbek MA. Preservation of a remote fear memory requires new myelin formation. Nat Neurosci. 2020;23:487–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Du W, Deng Y, Jiang R, Tong L, Li R, Jiang X. Clemastine enhances myelination, delays axonal loss and promotes functional recovery in spinal cord injury. Neurochem Res. 2022;47:503–15.

    Article  CAS  PubMed  Google Scholar 

  37. Li Z, He Y, Fan S, Sun B. Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination. Neurosci Bull. 2015;31:617–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390:2481–9.

    Article  CAS  PubMed  Google Scholar 

  39. Drug Approval Package: VesiCare (Solifenacin Succinate) NDA #021518 [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-518_VesiCare.cfm. Accessed 25 Dec 2022.

  40. Kalin NH, Shelton SE. Defensive behaviors in infant rhesus monkeys: environmental cues and neurochemical regulation. Science. 1989;243:1718–21.

    Article  CAS  PubMed  Google Scholar 

  41. Kalin NH. The neurobiology of fear. Sci Am. 1993;268:94–101.

    Article  CAS  PubMed  Google Scholar 

  42. Fox AS, Oler JA, Shackman AJ, Shelton SE, Raveendran M, McKay DR, et al. Intergenerational neural mediators of early-life anxious temperament. Proc Natl Acad Sci. 2015;112:9118–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rosenbaum JF, Biederman J, Bolduc-Murphy EA, Faraone SV, Chaloff J, Hirshfeld DR, et al. Behavioral inhibition in childhood: a risk factor for anxiety disorders. Harv Rev Psychiatry. 1993;1:2–16.

    Article  CAS  PubMed  Google Scholar 

  44. Shackman AJ, Fox AS, Oler JA, Shelton SE, Oakes TR, Davidson RJ, et al. Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology. Mol Psychiatry. 2017;22:724–32.

    Article  CAS  PubMed  Google Scholar 

  45. Goldsmith HH, Hilton EC, Phan JM, Sarkisian KL, Carroll IC, Lemery-Chalfant K, et al. Childhood inhibition predicts adolescent social anxiety: findings from a longitudinal twin study. Dev Psychopathol. 2022;34:1666–85.

    Article  Google Scholar 

  46. Birn RM, Shackman AJ, Oler JA, Williams LE, McFarlin DR, Rogers GM, et al. Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety. Mol Psychiatry. 2014;19:915–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27–31.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Nair A, Morsy MA, Jacob S. Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug Dev Res. 2018;79:373–82.

    Article  CAS  PubMed  Google Scholar 

  49. Fox AS, Shelton SE, Oakes TR, Davidson RJ, Kalin NH. Trait-like brain activity during adolescence predicts anxious temperament in primates. PLoS One. 2008;3:e2570.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kecskemeti S, Samsonov A, Hurley SA, Dean DC, Field A, Alexander AL. MPnRAGE: a technique to simultaneously acquire hundreds of differently contrasted MPRAGE images with applications to quantitative T1 mapping. Magn Reson Med. 2015;75:1040–53.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Kecskemeti S, Samsonov A, Velikina J, Field AS, Turski P, Rowley H, et al. Robust motion correction strategy for structural mri in unsedated children demonstrated with three-dimensional radial MPnRAGE. Radiology. 2018;289:509–16.

    Article  PubMed  Google Scholar 

  52. Avants BB, Epstein CL, Grossman M, Gee JC. Symmetric diffeomorphic image registration with cross-correlation: Evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal. 2008;12:26–41.

    Article  CAS  PubMed  Google Scholar 

  53. Camino: Open-Source Diffusion-MRI Reconstruction and Processing − 02759.pdf [Internet]. Available from: https://afni.nimh.nih.gov/sscc/staff/rwcox/ISMRM_2006/ISMRM%202006%20-%203340/files/02759.pdf. Accessed 24 Jan 2021.

  54. Zhang H, Yushkevich P, Alexander D, Gee J. Deformable registration of diffusion tensor MR images with explicit orientation optimization. Med Image Anal. 2006;10:764–85.

    Article  PubMed  Google Scholar 

  55. Jenkinson M, Beckmann CF, Behrens TEJ, Woolrich MW, Smith SM. FSL. Neuroimage. 2012;62:782–90.

    Article  PubMed  Google Scholar 

  56. Brauer M, Curtin JJ. Linear mixed-effects models and the analysis of nonindependent data: a unified framework to analyze categorical and continuous independent variables that vary within-subjects and/or within-items. Psychol Methods. 2018;23:389–411.

    Article  PubMed  Google Scholar 

  57. Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res. 1996;29:162–73.

    Article  CAS  PubMed  Google Scholar 

  58. Cherubini A, Péran P, Hagberg GE, Varsi AE, Luccichenti G, Caltagirone C, et al. Characterization of white matter fiber bundles with T2* relaxometry and diffusion tensor imaging. Magn Reson Med. 2009;61:1066–72.

    Article  PubMed  Google Scholar 

  59. Moody JF, Aggarwal N, Dean DC, Tromp DPM, Kecskemeti SR, Oler JA, et al. Longitudinal assessment of early-life white matter development with quantitative relaxometry in nonhuman primates. Neuroimage. 2022;251:118989.

    Article  PubMed  Google Scholar 

  60. Marisca R, Hoche T, Agirre E, Hoodless LJ, Barkey W, Auer F, et al. Functionally distinct subgroups of oligodendrocyte precursor cells integrate neural activity and execute myelin formation. Nat Neurosci. 2020;23:363–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Levine JM, Reynolds R, Fawcett JW. The oligodendrocyte precursor cell in health and disease. Trends Neurosci. 2001;24:39–47.

    Article  CAS  PubMed  Google Scholar 

  62. Crawford AH, Stockley JH, Tripathi RB, Richardson WD, Franklin RJM. Oligodendrocyte progenitors: adult stem cells of the central nervous system? Exp Neurol. 2014;260:50–5.

    Article  CAS  PubMed  Google Scholar 

  63. Fernandez-Castaneda A, Gaultier A. Adult oligodendrocyte progenitor cells – multifaceted regulators of the CNS in health and disease. Brain Behav Immun. 2016;57:1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Clayton BLL, Tesar PJ. Oligodendrocyte progenitor cell fate and function in development and disease. Curr Opin Cell Biol. 2021;73:35–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhang SC, Ge B, Duncan ID. Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. Proc Natl Acad Sci. 1999;96:4089–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Deoni SCL. Quantitative relaxometry of the brain. Top Magn Reson Imaging. 2010;21:101–13.

    Article  PubMed  PubMed Central  Google Scholar 

  67. O’Muircheartaigh J, Vavasour I, Ljungberg E, Li DKB, Rauscher A, Levesque V, et al. Quantitative neuroimaging measures of myelin in the healthy brain and in multiple sclerosis. Hum Brain Mapp. 2019;40:2104–16.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Kumar R, Nguyen HD, Macey PM, Woo MA, Harper RM. Regional brain axial and radial diffusivity changes during development. J Neurosci Res. 2012;90:346–55.

    Article  CAS  PubMed  Google Scholar 

  69. Winklewski PJ, Sabisz A, Naumczyk P, Jodzio K, Szurowska E, Szarmach A. Understanding the physiopathology behind axial and radial diffusivity changes—what do we know? Front Neurol. 2018;9:92.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Alexander AL, Lee JE, Lazar M, Field AS. Diffusion tensor imaging of the brain. Neurotherapeutics. 2007;4:1–14.

    Article  Google Scholar 

  71. Kalin NH, Fox AS, Kovner R, Riedel MK, Fekete EM, Roseboom PH, et al. Overexpressing corticotropin-releasing factor in the primate amygdala increases anxious temperament and alters its neural circuit. Biol Psychiatry. 2016;80:345–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006;63:1121–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sipos ML, Burchnell V, Galbicka G. Dose-response curves and time-course effects of selected anticholinergics on locomotor activity in rats. Psychopharmacology 1999;147:250–6.

    Article  CAS  PubMed  Google Scholar 

  74. Scarr E. Muscarinic receptors: their roles in disorders of the central nervous system and potential as therapeutic targets. CNS Neurosci Ther. 2012;18:369–79.

    Article  CAS  PubMed  Google Scholar 

  75. Yamada M, Miyakawa T, Duttaroy A, Yamanaka A, Moriguchi T, Makita R, et al. Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature. 2001;410:207–12.

    Article  CAS  PubMed  Google Scholar 

  76. Cerghet M, Skoff RP, Swamydas M, Bessert D. Sexual dimorphism in the white matter of rodents. J Neurol Sci. 2009;286:76–80.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Yasuda K, Maki T, Kinoshita H, Kaji S, Toyokawa M, Nishigori R, et al. Sex-specific differences in transcriptomic profiles and cellular characteristics of oligodendrocyte precursor cells. Stem Cell Res. 2020;46:101866.

    Article  CAS  PubMed  Google Scholar 

  78. Swamydas M, Bessert D, Skoff R. Sexual dimorphism of oligodendrocytes is mediated by differential regulation of signaling pathways. J Neurosci Res. 2009;87:3306–19.

  79. Fox AS, Kalin NH. A translational neuroscience approach to understanding the development of social anxiety disorder and its pathophysiology. Am J Psychiatry. 2014;171:1162–73.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. Jason F. Moody for his expertize and assistance with the quantitative relaxometry analyses, and Carissa Boettcher for assisting with the animal care and experimentation protocols. We also thank the many other members of the staffs of the Harlow Center for Biological Psychology and Wisconsin National Primate Research Center. This work was supported by grants from the National Institutes of Health: R01-MH081884 (NHK); R01-MH046729 (NHK)—includes NIH Bench-to-Bedside supplement (Award ID: 654199; MAB, NHK); T32-GM140935 (NA); T32-MH018931 (NA). The funding sources played no role in the conceptualization, design, execution, or analysis of any part of the study.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, 53719, USA

    Nakul Aggarwal, Jonathan A. Oler, Do P. M. Tromp, Patrick H. Roseboom, Marissa K. Riedel, Victoria R. Elam & Ned H. Kalin

  2. Neuroscience and Novel Therapeutics Unit, National Institute of Mental Health, Bethesda, MD, 20892, USA

    Melissa A. Brotman

Authors
  1. Nakul Aggarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan A. Oler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Do P. M. Tromp
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrick H. Roseboom
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marissa K. Riedel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Victoria R. Elam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Melissa A. Brotman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ned H. Kalin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NA, JAO, DPMT, PHR, MKR, VRE, MAB, and NHK all made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. NA and NHK drafted the work, and all authors contributed to critically revising the draft for important intellectual content and provided final approval of the version to be published. NA and NHK agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Nakul Aggarwal.

Ethics declarations

Competing interests

NHK reported receiving grants from the National Institute of Mental Health; consulting to CME Outfitters, the Pritzker Neuropsychiatric Disorders Research Consortium, the Skyland Trail Advisory Board, the Early Life Adversity Research External Scientific Advisory Board at the University of Texas at Austin, and Corcept Therapeutics Incorporated; and serving as editor-in-chief of The American Journal of Psychiatry during the conduct of the study. The other authors report no potential conflicts of interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aggarwal, N., Oler, J.A., Tromp, D.P.M. et al. A preliminary study of the effects of an antimuscarinic agent on anxious behaviors and white matter microarchitecture in nonhuman primates. Neuropsychopharmacol. 49, 405–413 (2024). https://doi.org/10.1038/s41386-023-01686-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41386-023-01686-1

Search

Advanced search

Quick links