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Effects of arginine vasopressin on human anxiety and associations with sex, dose, and V1a-receptor genotype

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Abstract

Rationale

Arginine vasopressin (AVP) has dose- and sex-specific effects on social behavior, and variation in social responses is related to variation in the V1a receptor gene in animals. Whether such complexity also characterizes AVP effects on anxiety in humans, or whether V1a genotype is related to anxiety and/or AVP’s ability to affect it, remains to be determined.

Objective

To test if AVP has dose-dependent effects on anxiety in men and/or women and if a particular allele within the RS3 promoter region of the V1a receptor gene is associated with anxiety and/or AVP effects on anxiety.

Method

Men and women self-administered 20 IU or 40 IU intranasal arginine vasopressin (AVP) and placebo in a double-blind, within-subjects design, and State (SA) and Trait (TA) anxiety were measured 60 min later. PCR was used to identify allelic variation within the RS3 region of the V1a receptor gene.

Results

AVP decreased SA in men across both doses, whereas only the lower dose had the same effect, across sexes, in individuals who carry at least one copy of a previously identified “risk” allele in the RS3 promoter of the V1a receptor gene. Additionally, after placebo, women who carried a copy of the allele displayed lower TA than women who did not, and AVP acutely increased TA scores in those women.

Conclusions

Exogenous AVP has modest sex- and dose-dependent effects on anxiety/affect in humans. Further, allelic variation in the V1a promoter appears associated with responsiveness to AVP’s effects and, at least in women, to stable levels of anxiety/affect.

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References

  • Albers HE (2015) Species, sex and individual differences in the vasotocin/vasopressin system: relationship to neurochemical signaling in the social behavior neural network. Front Neuroendocrinol 36:49–71

    Article  CAS  PubMed  Google Scholar 

  • Avinun R, Israel S, Shalev I, Gritsenko I, Bornstein G, Ebstein RP et al (2011) AVPR1A variant associated with preschoolers’ lower altruistic behavior. PLoS One 6(9):e25274

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Avinun R, Ebstein RP, Knafo A (2012) Human maternal behaviour is associated with arginine vasopressin receptor 1A gene. Biol Lett 8(5):894–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balsamo M, Romanelli R, Innamoratti M, Ciccarese G, Carlucci L, Saggino A (2013) The State-Trait Anxiety Inventory: shadows and lights on its construct validity. J Psychopathol Behav Assess 35:475–486

    Article  Google Scholar 

  • Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K et al (1994) Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry 151(8):1132–1136

    Article  CAS  PubMed  Google Scholar 

  • Bieling PJ, Antony MM, Swinson RP (1998) The State-Trait Anxiety Inventory, Trait version: structure and content re-examined. Behav Res Ther 36(7–8):777–788

    Article  CAS  PubMed  Google Scholar 

  • Born J, Fehm-Wolfsdorf G, Lutzenberger W, Voigt KH, Fehm HL (1986) Vasopressin and electrophysiological signs of attention in man. Peptides 7(2):189–193

    Article  CAS  PubMed  Google Scholar 

  • Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL (2002) Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 5(6):514–516

    Article  CAS  PubMed  Google Scholar 

  • Bredewold R, Veenema AH (2018) Sex differences in the regulation of social and anxiety-related behaviors: insights from vasopressin and oxytocin brain systems. Curr Opin Neurobiol 49:132–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruins J, Hijman R, Van Ree JM (1992) Effect of a single dose of des-glycinamide-[Arg8]vasopressin or oxytocin on cognitive processes in young healthy subjects. Peptides 13(3):461–468

    Article  CAS  PubMed  Google Scholar 

  • Brydges NM, Hall J, Best C, Rule L, Watkin H, Drake AJ et al (2019) Childhood stress impairs social function through AVP-dependent mechanisms. Transl Psychiatry 9(1):330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caldwell HK, Albers HE (2004) Photoperiodic regulation of vasopressin receptor binding in female Syrian hamsters. Brain Res 1002(1–2):136–141

    Article  CAS  PubMed  Google Scholar 

  • Cho MM, DeVries AC, Williams JR, Carter CS (1999) The effects of oxytocin and vasopressin on partner preferences in male and female prairie voles (Microtus ochrogaster). Behav Neurosci 113(5):1071–1079

    Article  CAS  PubMed  Google Scholar 

  • Churchland PS, Winkielman P (2012) Modulating social behavior with oxytocin: how does it work? What does it mean? Horm Behav 61(3):392–399

    Article  CAS  PubMed  Google Scholar 

  • de Vries GJ, Duetz W, Buijs RM, van Heerikhuize J, Vreeburg JT (1986) Effects of androgens and estrogens on the vasopressin and oxytocin innervation of the adult rat brain. Brain Res 399(2):296–302

    Article  PubMed  Google Scholar 

  • Dodt C, Pietrowsky R, Sewing A, Zabel A, Fehm HL, Born J (1994) Effects of vasopressin on event-related potential indicators of cognitive stimulus processing in young and old humans. J Gerontol 49(4):M183-188

    Article  CAS  PubMed  Google Scholar 

  • Dumais KM, Veenema AH (2016) Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol 40:1–23

    Article  CAS  PubMed  Google Scholar 

  • Ehlert U, Straub R (1998) Physiological and emotional response to psychological stressors in psychiatric and psychosomatic disorders. Ann N Y Acad Sci 851:477–486

    Article  CAS  PubMed  ADS  Google Scholar 

  • Fehm-Wolfsdorf G, Bachholz G, Born J, Voigt K, Fehm HL (1988) Vasopressin but not oxytocin enhances cortical arousal: an integrative hypothesis on behavioral effects of neurohypophyseal hormones. Psychopharmacology 94(4):496–500

    Article  CAS  PubMed  Google Scholar 

  • Feng C, DeMarco AC, Haroon E, Rilling JK (2015) Neuroticism modulates the effects of intranasal vasopressin treatment on the neural response to positive and negative social interactions. Neuropsychologia 73:108–115

    Article  PubMed  PubMed Central  Google Scholar 

  • Feng C, Hackett PD, DeMarco AC, Chen X, Stair S, Haroon E et al (2015) Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans. Brain Imaging Behav 9(4):754–764

    Article  PubMed  Google Scholar 

  • Feng C, Qin L, Luo Y, Xu P (2020) Intranasal vasopressin expedites dishonesty in women. Horm Behav 126:104843

    Article  CAS  PubMed  Google Scholar 

  • Forsling ML, Stromberg P, Akerlund M (1982) Effect of ovarian steroids on vasopressin secretion. J Endocrinol 95(1):147–151

    Article  CAS  PubMed  Google Scholar 

  • Freeman AR, Hare JF, Anderson WG, Caldwell HK (2018) Effects of arginine vasopressin on Richardson’s ground squirrel social and vocal behavior. Behav Neurosci 132(1):34–50

    Article  PubMed  Google Scholar 

  • Garcia-Sifuentes Y, Maney DL (2021) Reporting and misreporting of sex differences in the biological sciences. Elife 10

  • Golimbet V, Alfimova M, Abramova L, Kaleda V, Gritsenko I (2015) Arginine vasopressin 1a receptor RS3 promoter microsatellites in schizophrenia: a study of the effect of the “risk” allele on clinical symptoms and facial affect recognition. Psychiatry Res 225(3):739–740

    Article  CAS  PubMed  Google Scholar 

  • Gozzi M, Dashow EM, Thurm A, Swedo SE, Zink CF (2017) Effects of oxytocin and vasopressin on preferential brain responses to negative social feedback. Neuropsychopharmacology 42(7):1409–1419

    Article  CAS  PubMed  Google Scholar 

  • Greer ER, Caldwell JD, Johnson MF, Prange AJ Jr, Pedersen CA (1986) Variations in concentration of oxytocin and vasopressin in the paraventricular nucleus of the hypothalamus during the estrous cycle in rats. Life Sci 38(25):2311–2318

    Article  CAS  PubMed  Google Scholar 

  • Guastella AJ, Kenyon AR, Alvares GA, Carson DS, Hickie IB (2010) Intranasal arginine vasopressin enhances the encoding of happy and angry faces in humans. Biol Psychiatry 67(12):1220–1222

    Article  CAS  PubMed  Google Scholar 

  • Guastella AJ, Kenyon AR, Unkelbach C, Alvares GA, Hickie IB (2011) Arginine vasopressin selectively enhances recognition of sexual cues in male humans. Psychoneuroendocrinology 36(2):294–297

    Article  CAS  PubMed  Google Scholar 

  • Hopkins WD, Donaldson ZR, Young LJ (2012) A polymorphic indel containing the RS3 microsatellite in the 5′ flanking region of the vasopressin V1a receptor gene is associated with chimpanzee (Pan troglodytes) personality. Genes Brain Behav 11(5):552–558

    Article  CAS  PubMed  Google Scholar 

  • Kajantie E, Phillips DI (2006) The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology 31(2):151–178

    Article  CAS  PubMed  Google Scholar 

  • Kim SJ, Young LJ, Gonen D, Veenstra-VanderWeele J, Courchesne R, Courchesne E et al (2002) Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism. Mol Psychiatry 7(5):503–507

    Article  CAS  PubMed  Google Scholar 

  • Knafo A, Israel S, Darvasi A, Bachner-Melman R, Uzefovsky F, Cohen L et al (2008) Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA. Genes Brain Behav 7(3):266–275

    Article  CAS  PubMed  Google Scholar 

  • Lago TR, Brownstein MJ, Page E, Beydler E, Manbeck A, Beale A et al (2021) The novel vasopressin receptor (V1aR) antagonist SRX246 reduces anxiety in an experimental model in humans: a randomized proof-of-concept study. Psychopharmacology 238(9):2393–2403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Latzman RD, Hopkins WD, Keebaugh AC, Young LJ (2014) Personality in chimpanzees (Pan troglodytes): exploring the hierarchical structure and associations with the vasopressin V1A receptor gene. PLoS One 9(4):e95741

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  • Latzman RD, Schapiro SJ, Hopkins WD (2017) Triarchic psychopathy dimensions in chimpanzees (Pan troglodytes): investigating associations with genetic variation in the vasopressin receptor 1A gene. Front Neurosci 11:407

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee RJ, Coccaro EF, Cremers H, McCarron R, Lu SF, Brownstein MJ et al (2013) A novel V1a receptor antagonist blocks vasopressin-induced changes in the CNS response to emotional stimuli: an fMRI study. Front Syst Neurosci 7:100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu JJ, Lou F, Lavebratt C, Forsell Y (2015) Impact of childhood adversity and vasopressin receptor 1a variation on social interaction in adulthood: a cross-sectional study. PLoS One 10(8):e0136436

    Article  PubMed  PubMed Central  Google Scholar 

  • Marshall AD (2013) Posttraumatic stress disorder and partner-specific social cognition: a pilot study of sex differences in the impact of arginine vasopressin. Biol Psychol 93(2):296–303

    Article  PubMed  PubMed Central  Google Scholar 

  • Massa MG, Aghi K, Hill MJ (2023) Deconstructing sex: strategies for undoing binary thinking in neuroendocrinology and behavior. Horm Behav 156:105441

    Article  PubMed  Google Scholar 

  • Meyer-Lindenberg A, Kolachana B, Gold B, Olsh A, Nicodemus KK, Mattay V et al (2009) Genetic variants in AVPR1A linked to autism predict amygdala activation and personality traits in healthy humans. Mol Psychiatry 14(10):968–975

    Article  CAS  PubMed  Google Scholar 

  • Neto ML, Antunes M, Lopes M, Ferreira D, Rilling J, Prata D (2020) Oxytocin and vasopressin modulation of prisoner’s dilemma strategies. J Psychopharmacol 34(8):891–900

    Article  PubMed  PubMed Central  Google Scholar 

  • Neumann ID, Landgraf R (2012) Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 35(11):649–659

    Article  CAS  PubMed  Google Scholar 

  • Pappa I, St Pourcain B, Benke K, Cavadino A, Hakulinen C, Nivard MG et al (2016) A genome-wide approach to children’s aggressive behavior: The EAGLE consortium. Am J Med Genet B Neuropsychiatr Genet 171(5):562–572

    Article  CAS  PubMed  Google Scholar 

  • Parker KJ, Oztan O, Libove RA, Mohsin N, Karhson DS, Sumiyoshi RD et al (2019) A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism. Sci Transl Med 11(491).

  • Poulin MJ, Holman EA, Buffone A (2012) The neurogenetics of nice: receptor genes for oxytocin and vasopressin interact with threat to predict prosocial behavior. Psychol Sci 23(5):446–452

    Article  PubMed  Google Scholar 

  • Price D, Burris D, Cloutier A, Thompson CB, Rilling JK, Thompson RR (2017) Dose-dependent and lasting influences of intranasal vasopressin on face processing in men. Front Endocrinol (lausanne) 8:220

    Article  PubMed  Google Scholar 

  • Rigney N, Whylings J, de Vries GJ, Petrulis A (2021) Sex Differences in the control of social investigation and anxiety by vasopressin cells of the paraventricular nucleus of the hypothalamus. Neuroendocrinology 111(6):521–535

    Article  CAS  PubMed  Google Scholar 

  • Rilling JK, DeMarco AC, Hackett PD, Thompson R, Ditzen B, Patel R et al (2012) Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men. Psychoneuroendocrinology 37(4):447–461

    Article  CAS  PubMed  Google Scholar 

  • Rilling JK, DeMarco AC, Hackett PD, Chen X, Gautam P, Stair S et al (2014) Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 39:237–248

    Article  CAS  PubMed  Google Scholar 

  • Rilling JK, Li T, Chen X, Gautam P, Haroon E, Thompson RR (2017) Arginine vasopressin effects on subjective judgments and neural responses to same and other-sex faces in men and women. Front Endocrinol (lausanne) 8:200

    Article  PubMed  Google Scholar 

  • Schneider BA, Avivi-Reich M, Mozuraitis M (2015) A cautionary note on the use of the Analysis of Covariance (ANCOVA) in classification designs with and without within-subject factors. Front Psychol 6:474

    Article  PubMed  PubMed Central  Google Scholar 

  • Skowsky WR, Swan L, Smith P (1979) Effects of sex steroid hormones on arginine vasopressin in intact and castrated male and female rats. Endocrinology 104(1):105–108

    Article  CAS  PubMed  Google Scholar 

  • Smiley KO, Munley KM, Aghi K, Lipshutz SE, Patton TM, Pradhan DS et al (2023) Sex diversity in the 21st century: concepts, frameworks, and approaches for the future of neuroendocrinology. Horm Behav 157:105445

    Article  PubMed  Google Scholar 

  • Spielberg JM, Schwarz JM, Matyi MA (2019) Anxiety in transition: Neuroendocrine mechanisms supporting the development of anxiety pathology in adolescence and young adulthood. Front Neuroendocrinol 55:100791

    Article  PubMed  PubMed Central  Google Scholar 

  • Spielberger JM, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA (1983) Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press

    Google Scholar 

  • Staes N, Weiss A, Helsen P, Korody M, Eens M, Stevens JMG (2016) Bonobo personality traits are heritable and associated with vasopressin receptor gene 1a variation. Sci Rep 6:38193

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Tansey KE, Hill MJ, Cochrane LE, Gill M, Anney RJ, Gallagher L (2011) Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism. Mol Autism 2(1):3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thompson RR, George K, Walton JC, Orr SP, Benson J (2006) Sex-specific influences of vasopressin on human social communication. Proc Natl Acad Sci U S A 103(20):7889–7894

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Uzun N, Akca OF, Kilinc I, Balci T (2022) Oxytocin and vasopressin levels and related factors in adolescents with social phobia and other anxiety disorders. Clin Psychopharmacol Neurosci 20(2):330–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Leeuwen FW, Caffe AR, De Vries GJ (1985) Vasopressin cells in the bed nucleus of the stria terminalis of the rat: sex differences and the influence of androgens. Brain Res 325(1–2):391–394

    Article  PubMed  Google Scholar 

  • Vollebregt O, Koyama E, Zai CC, Shaikh SA, Lisoway AJ, Kennedy JL et al (2021) Evidence for association of vasopressin receptor 1A promoter region repeat with childhood onset aggression. J Psychiatr Res 140:522–528

    Article  PubMed  Google Scholar 

  • Walum H, Westberg L, Henningsson S, Neiderhiser JM, Reiss D, Igl W et al (2008) Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans. Proc Natl Acad Sci U S A 105(37):14153–14156

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Wang J, Qin W, Liu F, Liu B, Zhou Y, Jiang T et al (2016) Sex-specific mediation effect of the right fusiform face area volume on the association between variants in repeat length of AVPR1A RS3 and altruistic behavior in healthy adults. Hum Brain Mapp 37(7):2700–2709

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu X, Feng C, He Z, Gong X, Luo YJ, Luo Y (2019) Gender-specific effects of vasopressin on human social communication: An ERP study. Horm Behav 113:85–94

    Article  CAS  PubMed  Google Scholar 

  • Yang FJ, Ma L, Yang J, Zhu ZL, Wang CH (2019) Intranasal vasopressin relieves orthopedic pain after surgery. Pain Manag Nurs 20(2):126–132

    Article  PubMed  Google Scholar 

  • Yao S, Kendrick KM (2022) Effects of intranasal administration of oxytocin and vasopressin on social cognition and potential routes and mechanisms of action. Pharmaceutics 14(2)

  • Young LJ, Wang Z, Cooper TT, Albers HE (2000) Vasopressin (V1a) receptor binding, mRNA expression and transcriptional regulation by androgen in the Syrian hamster brain. J Neuroendocrinol 12(12):1179–1185

    Article  CAS  PubMed  Google Scholar 

  • Zhang-James Y, Fernandez-Castillo N, Hess JL, Malki K, Glatt SJ, Cormand B et al (2019) An integrated analysis of genes and functional pathways for aggression in human and rodent models. Mol Psychiatry 24(11):1655–1667

    Article  CAS  PubMed  Google Scholar 

  • Zhuang Q, Zheng X, Becker B, Lei W, Xu X, Kendrick KM (2021) Intranasal vasopressin like oxytocin increases social attention by influencing top-down control, but additionally enhances bottom-up control. Psychoneuroendocrinology 133:105412

    Article  PubMed  Google Scholar 

  • Zink CF, Kempf L, Hakimi S, Rainey CA, Stein JL, Meyer-Lindenberg A (2011) Vasopressin modulates social recognition-related activity in the left temporoparietal junction in humans. Transl Psychiatry 1:e3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Genotyping was done by Adriana Lori, Ph.D. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA. We thank Carol Thompson, Associate Scientist at the Johns Hopkins Biostatistical Center, for consultation for the statistical analyses. We are especially grateful for Cecilia R Price’s help with data organization.

Funding

This work was supported by NIMH award 5R01MH087721-05.

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Authors and Affiliations

  1. Division of Social Sciences, Oxford College of Emory University, Oxford, GA, 30054, USA

    R. R. Thompson

  2. Neuroscience Program, Bowdoin College, Brunswick, ME, 04011, USA

    R. R. Thompson

  3. Department of Psychiatry, Maine Medical Center, Portland, ME, USA

    D. Price, D. Burris & A. Cloutier

  4. Department of Psychology, Emory University, Atalanta, USA

    J. K. Rilling

  5. Department of Psychiatry and Behavioral Sciences, Emory University, Atalanta, USA

    J. K. Rilling

  6. Center for Behavioral Neuroscience, Emory University, Atalanta, USA

    J. K. Rilling

  7. Emory National Primate Research Center, Emory University, Atalanta, USA

    J. K. Rilling

  8. Center for Translational Social Neuroscience, Emory University, Atalanta, USA

    J. K. Rilling

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Thompson, R.R., Price, D., Burris, D. et al. Effects of arginine vasopressin on human anxiety and associations with sex, dose, and V1a-receptor genotype. Psychopharmacology (2024). https://doi.org/10.1007/s00213-024-06551-7

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