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Oxytocin increases anxiety to unpredictable threat

Molecular Psychiatry volume 18, pages 958–960 (2013)Cite this article

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The nonapeptide oxytocin (OT), dubbed by the media as the ‘moral’ or ‘love’ molecule, has a variety of pro-social effects across species. A relatively simple explanation for these complex effects is that OT alleviates anxiety,1 thereby indirectly promoting trust, cooperation and other affiliative behaviors.2, 3 Indeed, OT can reduce anxiety-like behavior in animals, via its neuromodulatory influence on the amygdala, a core hub mediating fear and anxiety.4 Surprisingly, OT also promotes territoriality, aggression and other defensive behaviors toward out-group members,2 complicating any straightforward interpretation of OT’s socio-emotional effects. Here, we show that OT does not reduce but rather increases defensive responding to unpredictable threat in humans, suggesting that OT enhances anxiety.

A critical distinction has been recognized between two kinds of defensive states, sustained anxiety and phasic fear.5 Although the former is elicited by ambiguity and uncertainty (that is, unpredictable threat), the latter is evoked by explicit threat cues (that is, predictable threat).5 The hypothesis that OT differentially modulates defensive responses to unpredictable versus predictable threats directly follows evidence that OT released from the paraventricular nucleus of the hypothalamus facilitates excitatory signaling in the bed nucleus of the stria terminalis (BNST),7, 8 a critical structure mediating defensive responses to unpredictable threats.5 In addition, OT receptor density varies by subdivision within the central nucleus of the rodent amygdala (CeA)4, 6 and these subdivisions are differentially involved in defensive responses to predictable (fear) and unpredictable threats (anxiety). The medial CeA (mCeA) and lateral CeA (lCeA) are involved in fear and anxiety,5 respectively, but only the lCeA is rich in OT receptors.6 Finally, while in rodents endogenous OT reduces freezing to a fear conditioned cue,8 systemic OT administration does not affect fear-potentiated startle to a threat cue.9 Accordingly, we tested the possibility that OT may selectively increase defensive responding to unpredictable but not predictable threats using startle as a measure of fear and anxiety.5

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Acknowledgements

Financial support of this study was provided by the Intramural Research Program of the National Institute of Mental Health, Grant no. MH002798. The authors thank Dr Pine for his clinical coverage of this study.

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Authors and Affiliations

  1. Neurobiology of Fear and Anxiety Section, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA

    C Grillon, M Krimsky, D R Charney, K Vytal & B Cornwell

  2. Emotional Development and Affective Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA

    M Ernst

Authors
  1. C Grillon
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  2. M Krimsky
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  3. D R Charney
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  4. K Vytal
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  5. M Ernst
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  6. B Cornwell
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Correspondence to C Grillon.

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Grillon, C., Krimsky, M., Charney, D. et al. Oxytocin increases anxiety to unpredictable threat. Mol Psychiatry 18, 958–960 (2013). https://doi.org/10.1038/mp.2012.156

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