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Alterations in adolescent brain serotonin (5HT)1A, 5HT2A, and dopamine (D)2 receptor systems in a nonhuman primate model of early life adversity

Neuropsychopharmacology (2024)Cite this article

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Abstract

Stress affects brain serotonin (5HT) and dopamine (DA) function, and the effectiveness of 5HT and DA to regulate stress and emotional responses. However, our understanding of the long-term impact of early life adversity (ELA) on primate brain monoaminergic systems during adolescence is scarce and inconsistent. Filling this gap in the literature is critical, given that the emergence of psychopathology during adolescence has been related to deficits in these systems. Here, we use a translational nonhuman primate (NHP) model of ELA (infant maltreatment by the mother) to examine the long-term impact of ELA on adolescent 5HT1A, 5HT2A and D2 receptor systems. These receptor systems were chosen based on their involvement in stress/emotional control, as well as reward and reinforcement. Rates of maternal abuse, rejection, and infant’s vocalizations were obtained during the first three postnatal months, and hair cortisol concentrations obtained at 6 months postnatal were examined as early predictors of binding potential (BP) values obtained during adolescence using positron emission tomography (PET) imaging. Maltreated animals demonstrated significantly lower 5HT1A receptor BP in prefrontal cortical areas as well as the amygdala and hippocampus, and lower 5HT2A receptor BP in striatal and prefrontal cortical areas. Maltreated animals also demonstrated significantly lower D2 BP in the amygdala. None of the behavioral and neuroendocrine measurements obtained early in life predicted any changes in BP data. Our findings suggest that early caregiving experiences regulate the development of brain 5HT and DA systems in primates, resulting in long-term effects evident during adolescence.

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Fig. 1: 5HT1A Receptor BPND.
Fig. 2: 5HT2A Receptor BPND.
Fig. 3: 5HT2A Receptor BPND in OFC and Putamen.
Fig. 4: D2 Receptor BPND.

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Acknowledgements

These data were reported in abstract form at the American College for Neuropsychopharmacology in 2018, as well as the College on Problems of Drug Dependence in 2018. The authors want to thank Brittany Howell, Anne Glenn, Christine Marsteller, Dora Guzman, Erin Siebert, and the staff at the Emory National Primate Research Center (ENPRC) for their contributions, excellent technical support and animal care provided during these studies. In addition, we thank Dr. Melinda Higgins for Biostatistical guidance and support.

Funding

This work was supported by funding from NIH/NIDA grant DA038588 and NIH/NIMH grant MH078105, as well as by the Emory National Primate Research Center (ENPRC) grant No. ORIP/OD P51OD011132 (ENPRC Base grant; the ENPRC is supported by the NIH, Office of Research Infrastructure Programs/OD [P51OD011132]) and by the Emory HPLC Bioanalytical Core (EHBC, which is supported by the Department of Pharmacology, Emory University School of Medicine and the Georgia Clinical & Translational Science Alliance of the NIH under Award Number UL1TR002378). The funders had no role in review design, data collection and analysis, decision to publish, or preparation of the manuscript; the content is solely the responsibility of the authors and does not represent the official views of the NIDA, NIMH or the NIH. The ENPRC is fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care, AAALAC, International.

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Authors and Affiliations

  1. Division of Neuropharmacology and Neurologic Diseases, Emory National Primate Research Center, Emory University, 954 Gatewood Rd NE, Atlanta, GA, 30329, USA

    Alison G. P. Wakeford & Leonard L. Howell

  2. Department of Psychiatry & Behavioral Sciences, Emory University, 12 Executive Park Dr NE #200, Atlanta, GA, 30329, USA

    Alison G. P. Wakeford, Elyse L. Morin, Leonard L. Howell & Mar M. Sanchez

  3. Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Rd. NE, Atlanta, GA, 30329, USA

    Jonathon A. Nye, Jiyoung Mun & Mark Goodman

  4. Division of Developmental and Cognitive Neuroscience, Emory National Primate Research Center, Emory University, 954 Gatewood Rd NE, Atlanta, GA, 30329, USA

    Elyse L. Morin & Mar M. Sanchez

  5. Department of Psychological & Brain Sciences, University of Massachusetts, 441 Tobin Hall, Amherst, MA, 01003, USA

    Jerrold S. Meyer

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AGPW collected data, conducted analyses, prepared figures, and wrote the manuscript. ELM, JM, and JSM conducted analyses and helped with manuscript preparation. JAN conducted analyses, designed part of these experiments, and revised this manuscript. MG, LLH, and MMS helped to design the experiment and revised the manuscript.

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Correspondence to Mar M. Sanchez.

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Wakeford, A.G.P., Nye, J.A., Morin, E.L. et al. Alterations in adolescent brain serotonin (5HT)1A, 5HT2A, and dopamine (D)2 receptor systems in a nonhuman primate model of early life adversity. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-023-01784-0

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  • DOI: https://doi.org/10.1038/s41386-023-01784-0

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