Abstract
Oxytocin reportedly decreases anxious feelings in humans and may therefore have therapeutic value for anxiety disorders, such as post-traumatic stress disorder (PTSD). As PTSD patients have exaggerated startle responses, a fear-potentiated startle paradigm in rats may have face validity as an animal model to examine the efficacy of oxytocin in treating these symptoms. Oxytocin (0, 0.01, 0.1, or 1.0 μg, subcutaneously) was given either 30 min before fear conditioning, immediately after fear conditioning, or 30 min before fear-potentiated startle testing to assess its effects on acquisition, consolidation, and expression of conditioned fear, respectively. Startle both in the presence and absence of the fear-conditioned light was significantly diminished by oxytocin when administered at acquisition, consolidation, or expression. There was no specific effect of oxytocin on light fear-potentiated startle. In an additional experiment, oxytocin had no effects on acoustic startle without previous fear conditioning. Further, in a context-conditioned test, previous light-shock fear conditioning did not increase acoustic startle during testing when the fear-conditioned light was not presented. The data suggest that oxytocin did not diminish cue-specific conditioned nor contextually conditioned fear, but reduced background anxiety. This suggests that oxytocin has unique effects of decreasing background anxiety without affecting learning and memory of a specific traumatic event. Oxytocin may have antianxiety properties that are particularly germane to the hypervigilance and exaggerated startle typically seen in PTSD patients.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Andari E, Duhamel J-R, Zalla T, Herbrecht E, Leboyer M, Sirigu A (2010). Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 107: 4389–4394.
Ayers LW, Missig G, Schulkin J, Rosen JB (2010). Systemic, but not intracerebroventricular, administration of oxytocin results in an attenuation of background anxiety in a fear-potentiated startle paradigm. Program No. 705.24. Society for Neuroscience: Neuroscience Meeting Planner, San Diego, CA. Online.
Baas JM, Grillon C, Bocker KB, Brack III AA, Morgan CA, Kenemans JL et al (2002). Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology 161: 233–247.
Boccia MM, Baratti CM (2000). Involvement of central cholinergic mechanisms in the effects of oxytocin and an oxytocin receptor antagonist on retention performance in mice. Neurobiol Learn Mem 74: 217–228.
Boccia MM, Kopf SR, Baratti CM (1998). Effects of a single administration of oxytocin or vasopressin and their interactions with two selective receptor antagonists on memory storage in mice. Neurobiol Learn Mem 69: 136–146.
Böcker KB, Baas JM, Kenemans JL, Verbaten MN (2001). Stimulus-preceding negativity induced by fear: a manifestation of affective anticipation. Int J Psychophysiol 43: 77–90.
Böcker KBE, Baas JMP, Kenemans JL, Verbaten MN (2004). Differences in startle modulation during instructed threat and selective attention. Biological Psychol 67: 343–358.
Braff DL, Geyer MA, Swerdlow NR (2001). Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156: 234–258.
Caldwell HK, Stephens SL, Young WS (2009). Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice. Mol Psychiatry 14: 190–196.
Carter CS (2007). Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders? Behav Brain Res 176: 170–186.
Davis M (1979). Diazepam and flurazepam: effects on conditioned fear as measured with the potentiated startle paradigm. Psychopharmacology (Berl) 62: 1–7.
Davis M (1989). Sensitization of the acoustic startle reflex by footshock. Behav Neurosci 103: 495–503.
Davis M, Falls WA, Campeau S, Kim M (1993). Fear-potentiated startle: a neural and pharmacological analysis. Behav Brain Res 58: 175–198.
Davis M, Walker DL, Miles L, Grillon C (2010). Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 35: 105–135.
de Jongh R, Groenink L, van der Gugten J, Olivier B (2003). Light-enhanced and fear-potentiated startle: temporal characteristics and effects of alpha-helical corticotropin-releasing hormone. Biol Psychiatry 54: 1041–1048.
de Oliveira LF, Camboim C, Diehl F, Consiglio AR, Quillfeldt JA (2007). Glucocorticoid-mediated effects of systemic oxytocin upon memory retrieval. Neurobiol Learn Mem 87: 67–71.
de Wied D, Gaffori O, Burbach JP, Kovacs GL, van Ree JM (1987). Structure activity relationship studies with C-terminal fragments of vasopressin and oxytocin on avoidance behaviors of rats. J Pharmacol Exp Ther 241: 268–274.
Di Simplicio M, Massey-Chase R, Cowen PJ, Harmer CJ (2009). Oxytocin enhances processing of positive vs negative emotional information in healthy male volunteers. J Psychopharmacol (Oxf) 23: 241–248.
Domes G, Heinrichs M, Gläscher J, Büchel C, Braus DF, Herpertz SC (2007). Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 62: 1187–1190.
Feifel D, Reza T (1999). Oxytocin modulates psychotomimetic-induced deficits in sensorimotor gating. Psychopharmacology (Berl) 141: 93–98.
Fendt M, Imobersteg S, Bürki H, McAllister KH, Sailer AW (2010). Intra-amygdala injections of neuropeptide S block fear-potentiated startle. Neurosci Lett 474: 154–157.
Fischer-Shofty M, Shamay-Tsoory SG, Harari H, Levkovitz Y (2010). The effect of intranasal administration of oxytocin on fear recognition. Neuropsychologia 48: 179–184.
Gimpl G, Fahrenholz F (2001). The oxytocin receptor system: structure, function, and regulation. Physiol Rev 81: 629–683.
Grillon C (2002). Startle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology. Biol Psychiatry 52: 958–975.
Grillon C, Ameli R, Goddard A, Woods SW, Davis M (1994). Baseline and fear-potentiated startle in panic disorder patients. Biol Psychiatry 35: 431–439.
Grillon C, Baas JMP, Pine DS, Lissek S, Lawley M, Ellis V et al (2006). The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle. Biol Psychiatry 60: 760–766.
Grillon C, Chavis C, Covington MF, Pine DS (2009a). Two-week treatment with the selective serotonin reuptake inhibitor citalopram reduces contextual anxiety but not cued fear in healthy volunteers: a fear-potentiated startle study. Neuropsychopharmacology 34: 964–971.
Grillon C, Morgan CA (1999). Fear-potentiated startle conditioning to explicit and contextual cues in Gulf War veterans with posttraumatic stress disorder. J Abnorm Psychol 108: 134–142.
Grillon C, Morgan III CA, Davis M, Southwick SM (1998). Effects of experimental context and explicit threat cues on acoustic startle in Vietnam veterans with posttraumatic stress disorder. Biol Psychiatry 44: 1027–1036.
Grillon C, Morgan CA, Southwick SM, Davis M, Charney DS (1996). Baseline startle amplitude and prepulse inhibition in Vietnam veterans with posttraumatic stress disorder. Psychiatry Res 64: 169–178.
Grillon C, Pine DS, Lissek S, Rabin S, Bonne O, Vythilingam M (2009b). Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder. Biol Psychiatry 66: 47–53.
Guastella AJ, Howard AL, Dadds MR, Mitchell P, Carson DS (2009). A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder. Psychoneuroendocrinology 34: 917–923.
Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U (2003). Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 54: 1389–1398.
Heinrichs M, von Dawans B, Domes G (2009). Oxytocin, vasopressin, and human social behavior. Front Neuroendocrinol 30: 548–557.
Jacobs NS, Cushman JD, Fanselow MS (2010). The accurate measurement of fear memory in Pavlovian conditioning: resolving the baseline issue. J Neurosci Methods 190: 235–239.
Joordens RJ, Hijzen TH, Olivier B (1998). The anxiolytic effect on the fear-potentiated startle is not due to a non-specific disruption. Life Sci 63: 2227–2232.
Jovanovic T, Norrholm SD, Blanding NQ, Phifer JE, Weiss T, Davis M et al (2010). Fear potentiation is associated with hypothalamic-pituitary-adrenal axis function in PTSD. Psychoneuroendocrinology 35: 846–857.
Jovanovic T, Norrholm SD, Fennell JE, Keyes M, Fiallos AM, Myers KM et al (2009). Posttraumatic stress disorder may be associated with impaired fear inhibition: relation to symptom severity. Psychiatry Res 167: 151–160.
Kehne JH, Cassella JV, Davis M (1988). Anxyolytic effects of buspirone and gepirone in the fear-potentiated startle paradigm. Psychopharmacology 94: 8–13.
King MG, Brown R, Kusnecov A (1985). An increase in startle response in rats administered oxytocin. Peptides 6: 567–568.
Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S et al (2005). Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25: 11489–11493.
Kiss A, Mikkelsen JD (2005). Oxytocin—anatomy and functional assignments: a minireview. Endocr Regul 39: 97–105.
Kovacs GL, Vecsei L, Telegdy G (1978). Opposite action of oxytocin to vasopressin in passive avoidance behavior in rats. Physiol Behav 20: 801–802.
Lee H-J, Caldwell HK, Macbeth AH, Tolu SG, Young WS (2008). A conditional knockout mouse line of the oxytocin receptor. Endocrinology 149: 3256–3263.
Liberzon I, Sripada CS (2008). The functional neuroanatomy of PTSD: a critical review. Prog Brain Res 167: 151–169.
Lundeberg T, Uvnas-Moberg K, Agren G, Bruzelius G (1994). Anti-nociceptive effects of oxytocin in rats and mice. Neurosci Let 170: 153–157.
Macdonald K, Macdonald TM (2010). The peptide that binds: a systematic review of oxytocin and its prosocial effects in humans. Harv Rev Psychiatry 18: 1–21.
Marazziti D, Catena Dell'osso M (2008). The role of oxytocin in neuropsychiatric disorders. Curr Med Chem 15: 698–704.
McNish KA, Gewirtz JC, Davis M (1997). Evidence of contextual fear after lesions of the hippocampus: a disruption of freezing but not fear-potentiated startle. J Neurosci 17: 9353–9360.
Morgan CA, Grillon C, Southwick SM, Davis M, Charney DS (1995). Fear-potentiated startle in posttraumatic stress disorder. Biol Psychiatry 38: 378–385.
Nair HP, Gutman AR, Davis M, Young LJ (2005). Central oxytocin, vasopressin, and corticotropin-releasing factor receptor densities in the basal forebrain predict isolation potentiated startle in rats. J Neurosci 25: 11479–11488.
Neumann ID (2008). Brain oxytocin: a key regulator of emotional and social behaviours in both females and males. J Neuroendocrinol 20: 858–865.
Petrovic P, Kalisch R, Singer T, Dolan RJ (2008). Oxytocin attenuates affective evaluations of conditioned faces and amygdala activity. J Neurosci 28: 6607–6615.
Pitman RK, Orr SP, Lasko NB (1993). Effects of intranasal vasopressin and oxytocin on physiologic responding during personal combat imagery in Vietnam veterans with posttraumatic stress disorder. Psychiatry Res 48: 107–117.
Rescorla RA, Wagner AR (1972). A theory of Pavlovian conditioning: variations in the effectiveness of reinforcement and non-reinforcement. In: Black AH, Prokasy W (eds). Classical Conditioning II: Current Research and Theory. Appleton-Century-Crofts: New York. pp 64–99.
Richardson R (2000). Shock sensitization of startle: learned or unlearned fear? Behav Brain Res 110: 109–117.
Ring RH, Malberg JE, Potestio L, Ping J, Boikess S, Luo B et al (2006). Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications. Psychopharmacology (Berl) 185: 218–225.
Ring RH, Schechter LE, Leonard SK, Dwyer JM, Platt BJ, Graf R et al (2010). Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist. Neuropharmacology 58: 69–77.
Risbrough VB, Brodkin JD, Geyer MA (2003). GABA-A and 5-HT1A receptor agonists block expression of fear-potentiated startle in mice. Neuropsychopharmacology 28: 654–663.
Risbrough VB, Geyer MA, Hauger RL, Coste S, Stenzel-Poore M, Wurst W et al (2009). CRF1 and CRF2 receptors are required for potentiated startle to contextual but not discrete cues. Neuropsychopharmacology 34: 1494–1503.
Rodrigues SM, Saslow LR, Garcia N, John OP, Keltner D (2009). Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans. Proc Natl Acad Sci USA 106: 21437–21441.
Rosen JB, Schulkin J (1998). From normal fear to pathological anxiety. Psychol Rev 105: 325–350.
Rotzinger S, Lovejoy DA, Tan LA (2010). Behavioral effects of neuropeptides in rodent models of depression and anxiety. Peptides 31: 736–756.
Rougemont-Bücking A, Linnman C, Zeffiro TA, Zeidan MA, Lebron-Milad K, Rodriguez-Romaguera J et al (2010). Altered processing of contextual information during fear extinction in PTSD: an fMRI Study. CNS Neurosci Ther, print copy in press (originally published online 16 April 2010, at http://www3.interscience.wiley.com/journal/119423678/).
Savaskan E, Ehrhardt R, Schulz A, Walter M, Schächinger H (2008). Post-learning intranasal oxytocin modulates human memory for facial identity. Psychoneuroendocrinology 33: 368–374.
Swerdlow NR, Weber M, Qu Y, Light GA, Braff DL (2008). Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology (Berl) 199: 331–388.
Uvnäs-Moberg K, Ahlenius S, Hillegaart V, Alster P (1994). High doses of oxytocin cause sedation and low doses cause an anxiolytic-like effect in male rats. Pharmacol Biochem Behav 49: 101–106.
Uvnäs-Moberg K, Björkstrand E, Salmi P, Johansson C, Astrand M, Ahlenius S (1999). Endocrine and behavioral traits in low-avoidance Sprague-Dawley rats. Regul Pept 80: 75–82.
Uvnäs-Moberg K, Eklund M, Hillegaart V, Ahlenius S (2000). Improved conditioned avoidance learning by oxytocin administration in high-emotional male Sprague-Dawley rats. Regul Pept 88: 27–32.
Vaidyanathan U, Patrick CJ, Cuthbert BN (2009). Linking dimensional models of internalizing psychopathology to neurobiological systems: affect-modulated startle as an indicator of fear and distress disorders and affiliated traits. Psychol Bull 135: 909–942.
Veening JG, de Jong T, Barendregt HP (2010). Oxytocin-messages via the cerebrospinal fluid: Behavioral effects; a review. Physiol Behav print copy in press (originally published online 20 May 2010, at http://www.sciencedirect.com/science/journal/00319384).
Walker DL, Davis M (2002a). Quantifying fear potentiated startle using absolute vs proportional increase scoring methods: implications for the neurocircuitry of fear and anxiety. Psychopharmacology (Berl) 164: 318–328.
Walker DL, Davis M (2002b). The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction. Pharmacol Biochem Behav 71: 379–392.
Winslow JT, Hearn EF, Ferguson J, Young LJ, Matzuk MM, Insel TR (2000). Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse. Horm Behav 37: 145–155.
Winslow JT, Noble PL, Davis M (2007). Modulation of fear-potentiated startle and vocalizations in juvenile rhesus monkeys by morphine, diazepam, and buspirone. Biol Psychiatry 61: 389–395.
Acknowledgements
This work was supported by Grant W81XWH-08-1-0182 from the Congressionally Directed Medical Research Programs, US Army Medical Research and Materiel Command.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Missig, G., Ayers, L., Schulkin, J. et al. Oxytocin Reduces Background Anxiety in a Fear-Potentiated Startle Paradigm. Neuropsychopharmacol 35, 2607–2616 (2010). https://doi.org/10.1038/npp.2010.155
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2010.155
Keywords
This article is cited by
-
Pharmacological modulation of conditioned fear in the fear-potentiated startle test: a systematic review and meta-analysis of animal studies
Psychopharmacology (2023)
-
Predictable maternal separation confers adult stress resilience via the medial prefrontal cortex oxytocin signaling pathway in rats
Molecular Psychiatry (2021)
-
Effects of intranasal insulin as an enhancer of fear extinction: a randomized, double-blind, placebo-controlled experimental study
Neuropsychopharmacology (2020)
-
Oxytocin receptors in the dorsolateral bed nucleus of the stria terminalis (BNST) bias fear learning toward temporally predictable cued fear
Translational Psychiatry (2019)
-
Oxytocin facilitates adaptive fear and attenuates anxiety responses in animal models and human studies—potential interaction with the corticotropin-releasing factor (CRF) system in the bed nucleus of the stria terminalis (BNST)
Cell and Tissue Research (2019)