Peripherally administered non-peptide oxytocin antagonist, L368,899®, accumulates in limbic brain areas: A new pharmacological tool for the study of social motivation in non-human primates
Open accessAbstract
Central administration of oxytocin (OT) antagonists inhibits maternal and sexual behavior in non-primates, providing the strongest experimental evidence that endogenous OT facilitates these behaviors. While there have been a few reports that ICV administration of OT increases social behaviors in monkeys, no studies to date have assessed the effects of OT antagonists. Therefore, we studied in rhesus monkeys whether L368,899, a non-peptide antagonist produced by Merck that selectively blocks the human uterine OT receptor, penetrates the CNS after peripheral administration and alters female maternal and sexual behavior. In two studies in four male monkeys, L368,899 was injected iv (1 mg/kg) after which (1) CSF samples were collected at intervals over 4 h and (2) brains were collected at 60 min. Assay of samples confirmed that iv-administered L368,899 entered CSF and accumulated in the hypothalamus, septum, orbitofrontal cortex, amygdala and hippocampus, but not other areas. An adult female monkey was tested for interest in either an infant or sexual behavior, receiving a different iv treatment prior to each test (1 or 3 mg/kg of L368,899 or saline). OT antagonist treatment reduced or eliminated interest in the infant and sexual behavior. These results, although preliminary, are the first to directly implicate endogenous OT in activation of primate maternal interest and sexual behavior. While it remains to be empirically demonstrated that peripherally administered L368,899 blocks central OT receptors, our behavioral findings suggest that this non-peptide antagonist may facilitate testing OT involvement in a variety of social and other behaviors in primates.
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After peripheral injection, L-368,899 has been reported to accumulate in limbic brain regions of rhesus macaques.
“The Merck compound L-368,899 is another small molecule OXTR antagonist that has been used in NHP studies (93), has excellent bioavailability after oral administration (94) and has been also reported to accumulate in limbic structures of the brains of rhesus macaques after peripheral injection (95).”
From Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications (2016) · cites this paper as [95]
L-368,899 readily passes through the brain-blood barrier.
“which readily passes through the brain-blood barrier (18, 19).”
From Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice (2018) · cites this paper as [18]
Systemically administered l-368,899 hydrochloride reaches the brain and preferentially binds with oxytocin receptors.
“Systemically administered l-368,899 hydrochloride is known to reach the brain, where it preferentially binds with oxytocin receptors75.”
From Oxytocin enhances observational fear in mice (2017) · cites this paper as [75]
The OTA L368,899 is readily absorbed by the bloodstream after passage through the digestive system, penetrates the CNS after peripheral administration, and accumulates in areas of the limbic system.
“The OTA (L368, 899; provided by Dr. Peter Williams, Merck & Co., Inc.) is readily absorbed by the bloodstream after passage through the digestive system (Thompson et al., 1997), penetrates the CNS after peripheral administration, and accumulates in areas of the limbic system (Boccia et al., 2007).”
From Oxytocin facilitates fidelity in well-established marmoset pairs by reducing sociosexual behavior toward opposite-sex strangers (2014) · cites this paper as Boccia et al., 2007
Cites
Oxytocin increases trust in humans
Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U., & Fehr, E. (2005) · Nature · doi:10.1038/nature03701 · Cited by 3,690 · see citing works
The oxytocin receptor system: structure, function, and regulation
Gimpl, G., & Fahrenholz, F. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.629 · Cited by 3,089 · see citing works
Dube, S. R., Felitti, V. J., Dong, M., Chapman, D. P., Giles, W. H., & Anda, R. F. (2003) · Pediatrics · doi:10.1542/peds.111.3.564 · Cited by 2,333 · see citing works
Heinrichs, M., Baumgartner, T., Kirschbaum, C., & Ehlert, U. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00465-7 · Cited by 2,091 · see citing works
Oxytocin Modulates Neural Circuitry for Social Cognition and Fear in Humans
Kirsch, P., Esslinger, C., Chen, Q., Mier, D., Lis, S., Siddhanti, S., Gruppe, H., Mattay, V. S., Gallhofer, B., & Meyer-Lindenberg, A. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.3984-05.2005 · Cited by 1,639 · see citing works
The neurobiology of pair bonding.
Young, L. J., & Wang, Z. (2004) · Nature Neuroscience · doi:10.1038/nn1327 · Cited by 1,523 · cited 1× · see citing works
“Central OT has been implicated in activation of social attachments, such as maternal behavior in rats and sheep (Pedersen, 1997; Kendrick, 2000) and pair-bonding in monogamous prairie voles (Insel et al 1997; Young and Wang, 2004).”
BackgroundSniffing neuropeptides: A transnasal approach to the human brain
Born, J., Lange, T., Kern, W., McGregor, G. P., Bickel, U., & Fehm, H. L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-849 · Cited by 1,356 · see citing works
Fries, A. B. W., Ziegler, T. E., Kurian, J. R., Jacoris, S., & Pollak, S. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504767102 · Cited by 570 · see citing works
Bale, T. L., Davis, A. M., Auger, A. P., Dorsa, D. M., & McCarthy, M. M. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-07-02546.2001 · Cited by 446 · see citing works
Neumann, I. D., Torner, L., & Wigger, A. (1999) · Neuroscience · doi:10.1016/s0306-4522(99)00433-9 · Cited by 402 · see citing works
Loup, F., Tribollet, E., Dubois-Dauphin, M., & Dreifuss, J. J. (1991) · Brain Research · doi:10.1016/0006-8993(91)90345-v · Cited by 378 · see citing works
Oxytocin, motherhood and bonding
Kendrick, K. M. (2000) · Experimental Physiology · doi:10.1111/j.1469-445x.2000.tb00014.x · Cited by 378 · see citing works
Lancaster, J. B. (1971) · Folia Primatologica · doi:10.1159/000155377 · Cited by 335 · see citing works
125I-labelled d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH29]OVT: a selective oxytocin receptor ligand
Elands, J., Barberis, C., Jard, S., Tribollet, E., Dreifuss, J.-J., Bankowski, K., Manning, M., & Sawyer, W. H. (1988) · European Journal of Pharmacology · doi:10.1016/0014-2999(88)90778-9 · Cited by 245 · see citing works
Analysis of Environmental Deprivation: Cognitive and Social Development in Romanian Orphans
Kaler, S. R., & Freeman, B. J. (1994) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.1994.tb01220.x · Cited by 189 · see citing works
The role of oxytocin and the paraventricular nucleus in the sexual behaviour of male mammals
Argiolas, A., & Melis, M. R. (2004) · Physiology & Behavior · doi:10.1016/j.physbeh.2004.08.019 · Cited by 177 · see citing works
Oxytocin Control of Maternal Behavior Regulation by Sex Steroids and Offspring Stimuli<sup>a</sup>
PEDERSEN, C. A. (1997) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1997.tb51916.x · Cited by 172 · see citing works
Self-citationWindle, R. J., Shanks, N., Lightman, S. L., & Ingram, C. D. (1997) · Endocrinology · doi:10.1210/en.138.7.2829 · Cited by 170 · see citing works
Neuropeptides and sexual behaviour
Argiolas, A. (1999) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(99)00068-8 · Cited by 148 · see citing works
Winslow, J., & Insel, T. (1991) · The Journal of Neuroscience · doi:10.1523/jneurosci.11-07-02032.1991 · Cited by 145 · see citing works
Loup, F., Tribollet, E., Dubois-Dauphin, M., Pizzolato, G., & Dreifuss, J. J. (1989) · Brain Research · doi:10.1016/0006-8993(89)90317-x · Cited by 136 · see citing works
Central oxytocin and reproductive behaviours
Insel, T. R. (1997) · Reviews of Reproduction · doi:10.1530/ror.0.0020028 · Cited by 129 · see citing works
Biology and ecology of parenting
Bornstein, M. H. (1995) · Lawrence Erlbaum Associates eBooks · Cited by 110 · see citing works
Bornstein, M. H. (2019) · Routledge eBooks · doi:10.4324/9780429401459 · Cited by 107 · see citing works
Aunts and Mothers: Adaptive Implications of Allomaternal Behavior of Nonhuman Primates
Quiatt, D. (1979) · American Anthropologist · doi:10.1525/aa.1979.81.2.02a00040 · Cited by 101 · see citing works
Bifulco, A. T., & Moran, P. M. (2002) · Routledge eBooks · doi:10.4324/9780203010976 · Cited by 91 · see citing works
Documented and Self-Reported Child Abuse and Adult Pain in a Community Sample
Brown, J. F., Berenson, K. R., & Cohen, P. R. (2005) · Clinical Journal of Pain · doi:10.1097/01.ajp.0000149797.16370.dc · Cited by 81 · see citing works
Goursaud, A. P., & Bachevalier, J. (2006) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.09.020 · Cited by 78 · see citing works
Self-citationMolecular characterization of a cloned human oxytocin receptor
Kimura, T., Makino, Y., Saji, F., Takemura, M., Inoue, T., Kikuchi, T., Kubota, Y., Azuma, C., Nobunaga, T., Tokugawa, Y., et al. (1994) · European Journal of Endocrinology · doi:10.1530/eje.0.1310385 · Cited by 77 · see citing works
Takemura, M., Kimura, T., Nomura, S., Makino, Y., Inoue, T., Kikuchi, T., Kubota, Y., Tokugawa, Y., Nobunaga, T., & Kamiura, S. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117236 · Cited by 75 · see citing works
Oxytocin and rodent sociosexual responses: from behavior to gene expression
M.Witt, D. (1995) · Neuroscience & Biobehavioral Reviews · doi:10.1016/0149-7634(95)00006-z · Cited by 64 · see citing works
Caldwell, J. D., Johns, J. M., Faggin, B. M., Senger, M., & Pendersen, C. A. (1994) · Hormones and Behavior · doi:10.1006/hbeh.1994.1024 · Cited by 63 · see citing works
Braun, S. (1998) · Cited by 56 · see citing works
Oxytocin decreases corticosterone and nociception and increases motor activity in OVX rats
Petersson, M., Eklund, M., & Uvnäs‐Moberg, K. (2004) · Maturitas · doi:10.1016/j.maturitas.2004.10.005 · Cited by 44 · see citing works
Are there oxytocin receptors in the primate brain?
TOLOCZKO, D. M., YOUNG, L., & INSEL, T. R. (1997) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1997.tb51953.x · Cited by 33 · see citing works
Discovery and development of non-peptide antagonists of peptide hormone receptors
Pettibone, D. J., & Freidinger, R. M. (1997) · Biochemical Society Transactions · doi:10.1042/bst0251051 · Cited by 23 · see citing works
Caine, N. G., & Mitchell, G. (1980) · International Journal of Primatology · doi:10.1007/bf02692277 · Cited by 22 · see citing works
Oxytocin receptors in non-human primate brain visualized with monoclonal antibody
Boccia, M. L., Panicker, A. K., Pedersen, C., & Petrusz, P. (2001) · Neuroreport · doi:10.1097/00001756-200106130-00041 · Cited by 21 · see citing works
Self-citationInfant kidnapping in rhesus monkeys ( macaca mulatta )
Guerra, R. F. (1989) · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The oxytocin receptor: from intracellular signaling to behavior
Jurek, B., & Neumann, I. D. (2018) · Physiological Reviews · doi:10.1152/physrev.00031.2017 · Cited by 999 · see citing works
MANNING, M., STOEV, S., CHINI, B., DURROUX, T., MOUILLAC, B., & GUILLON, G. (2008) · Progress in Brain Research · doi:10.1016/s0079-6123(08)00437-8 · Cited by 296 · see citing works
Smith, A. S., Ågmo, A., Birnie, A. K., & French, J. A. (2010) · Hormones and Behavior · doi:10.1016/j.yhbeh.2009.12.004 · Cited by 228 · see citing works
Freeman, S. M., & Young, L. J. (2016) · Journal of Neuroendocrinology · doi:10.1111/jne.12382 · Cited by 196 · see citing works
“The Merck compound L-368,899 is another small molecule OXTR antagonist that has been used in NHP studies (93), has excellent bioavailability after oral administration (94) and has been also reported to accumulate in limbic structures of the brains of rhesus macaques after peripheral injection (95).”
BackgroundNeuroendocrinology of social information processing in rats and mice
Choleris, E., Clipperton-Allen, A. E., Phan, A., & Kavaliers, M. (2009) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.05.003 · Cited by 205 · see citing works
Duque-Wilckens, N., Steinman, M. Q., Busnelli, M., Chini, B., Yokoyama, S., Pham, M., Laredo, S. A., Hao, R., Perkeybile, A. M., Minie, V. A., et al. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.08.024 · Cited by 181 · see citing works
Maestripieri, D., Hoffman, C. L., Anderson, G. M., Carter, C. S., & Higley, J. D. (2009) · Physiology & Behavior · doi:10.1016/j.physbeh.2008.12.016 · Cited by 174 · see citing works
Oxytocin enhances observational fear in mice
Pisansky, M. T., Hanson, L. R., Gottesman, I. I., & Gewirtz, J. C. (2017) · Nature Communications · doi:10.1038/s41467-017-02279-5 · Cited by 167 · see citing works
Oxytocin mediates entrainment of sensory stimuli to social cues of opposing valence
Choe, H. K., Reed, M. D., Benavidez, N., Montgomery, D., Soares, N., Yim, Y. S., & Choi, G. B. (2015) · Neuron · doi:10.1016/j.neuron.2015.06.022 · Cited by 124 · see citing works
Oxytocin Protects Hippocampal Memory and Plasticity from Uncontrollable Stress
Lee, S.-Y., Park, S.-H., Chung, C., Kim, J. J., Choi, S.-Y., & Han, J.-S. (2015) · Scientific Reports · doi:10.1038/srep18540 · Cited by 119 · see citing works
Role of oxytocin signaling in the regulation of body weight
Blevins, J. E., & Ho, J. M. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9260-x · Cited by 108 · see citing works
Olszewski, P. K., Klockars, A., Olszewska, A. M., Fredriksson, R., Schiöth, H. B., & Levine, A. S. (2010) · Endocrinology · doi:10.1210/en.2010-0151 · Cited by 104 · see citing works
Rocchetti, M., Radua, J., Paloyelis, Y., Xenaki, L., Frascarelli, M., Caverzasi, E., Politi, P., & Fusar‐Poli, P. (2014) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12185 · Cited by 83 · see citing works
Pup exposure facilitates retrieving behavior via the oxytocin neural system in female mice
Okabe, S., Tsuneoka, Y., Takahashi, A., Ooyama, R., Watarai, A., Maeda, S., Honda, Y., Nagasawa, M., Mogi, K., Nishimori, K., et al. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.01.036 · Cited by 82 · see citing works
Melis, M. R., Succu, S., Sanna, F., Boi, A., & Argiolas, A. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.06912.x · Cited by 72 · see citing works
Cavanaugh, J., Mustoe, A. C., Taylor, J. H., & French, J. A. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.06.020 · Cited by 72 · see citing works
Higham, J. P., Barr, C. S., Hoffman, C. L., Mandalaywala, T. M., Parker, K. J., & Maestripieri, D. (2011) · Behavioral Neuroscience · doi:10.1037/a0022695 · Cited by 69 · see citing works
“…ventricles of two female rhesus monkeys appeared to increase their interest in and affiliative behavior toward infants, whereas peripheral administration of an OT receptor antagonist that accumulated in the brain appeared to have the opposite effect in a single female (Boccia et al., 2007).”
InfluentialOxytocin modulates behavioral and physiological responses to a stressor in marmoset monkeys
Cavanaugh, J., Carp, S. B., Rock, C. M., & French, J. A. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.12.027 · Cited by 64 · see citing works
Do marmosets care to share? Oxytocin treatment reduces prosocial behavior toward strangers
Mustoe, A. C., Cavanaugh, J., Harnisch, A. M., Thompson, B. E., & French, J. A. (2015) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.04.015 · Cited by 59 · see citing works
Mustoe, A. C., Harnisch, A. M., Hochfelder, B., Cavanaugh, J., & French, J. A. (2016) · Animal Behaviour · doi:10.1016/j.anbehav.2016.01.025 · Cited by 40 · see citing works
Smith, A. L., Freeman, S. M., Voll, R. J., Young, L. J., & Goodman, M. M. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.10.116 · Cited by 38 · see citing works
Marmosets treated with oxytocin are more socially attractive to their long-term mate
Cavanaugh, J., Huffman, M. C., Harnisch, A. M., & French, J. A. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00251 · Cited by 36 · see citing works
An evolutionary perspective on the behavioral consequences of exogenous oxytocin application
Ebitz, R. B., & Platt, M. L. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2013.00225 · Cited by 35 · see citing works
Succu, S., Sanna, F., Argiolas, A., & Melis, M. R. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.03.026 · Cited by 35 · see citing works
Mooney, S. J., Coen, C. W., Holmes, M. M., & Beery, A. K. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.06.043 · Cited by 30 · see citing works
- Authors
- Boccia, M. L., Goursaud, A.-P. S., Bachevalier, J., Anderson, K. D., & Pedersen, C. A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Boccia, Maria L.
- Venue
- Hormones and Behavior
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 52
- Issue
- 3
- Pages
- 344-351
- ISSN
- 0018-506X (ISSN-L)
- PMC
- PMC2712625
- OpenAlex
- W2057372547
- Cited by
- 136
- References
- 39
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 8 · 2023: 7 · 2022: 8 · 2021: 12 · 2020: 5 · 2019: 6 · 2018: 9 · 2017: 10 · 2016: 6 · 2015: 12 · 2014: 14 · 2013: 7 · 2012: 5
- FWCI
- 6.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hormones and Behavior (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Emory University
- National Institutes of Health
- Yerkes National Primate Research Center, Emory University
- National Institute of Mental Health (R01MH061995, K01MH066217, MH06691)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD035471, HD35471)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Social Sciences › Psychology › Social Psychology › Primate Behavior and Ecology
- Keywords
- oxytocin, oxytocin receptor antagonist, non-peptide antagonists, rhesus monkeys, maternal behavior, sexual behavior, social motivation, brain distribution, cerebrospinal fluid, hypothalamus, amygdala, hippocampus, orbitofrontal cortex, septum, intravenous administration
- MeSH terms
- Amygdala, Animals, Blood-Brain Barrier, Camphanes, Female, Frontal Lobe, Hippocampus, Hormone Antagonists, Hypothalamus, Limbic System, Macaca mulatta, Male, Maternal Behavior, Oxytocin, Piperazines, Sexual Behavior, Animal, Septum of Brain
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