Kinetics and Dose Dependency of Intranasal Oxytocin Effects on Amygdala Reactivity

Spengler, Franny B.; Schultz, Johannes; Scheele, Dirk; Essel, Maximiliane; Maier, Wolfgang; Heinrichs, Markus; Hurlemann, René

doi:10.1016/j.biopsych.2017.04.015

Cited by 214 publications

(224 citation statements)

References 75 publications

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“…G s and G i activation typically result in opposite effects in terms of cellular function (58), meaning that in areas of high density of G i proteins higher amounts of OT may in fact result on inhibition of neuronal activity or null effects (50,57). The few studies inspecting the dose-response effects of intranasal OT, for example, on amygdala reactivity support this hypothesis by showing that deviating from an "optimal" dose may in fact result in null effects (38,59). This complexity might explain, for instance, why we did not observe changes in rCBF with the nebuliser in regions where the standard nasal spray produced effects.…”

Section: Discussionmentioning

confidence: 99%

“…First, we reasoned that if intranasal administration represents a privileged route for the 6 central delivery of OT, then intranasal-induced changes in rCBF in brain regions typically associated with the effects of OT in the brain (e.g. the amygdala) (37)(38)(39) should not be explained by increases in plasmatic OT achieved after OT intravenous infusion. Second, if posterior regions of the nasal cavity are involved in direct nose-to-brain transport, then using a device that can increase deposition in these areas may result in a more robust pattern of changes in rCBF when compared to OT administration with a standard nasal spray.…”

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confidence: 99%

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Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

Martins

Mazibuko

Zelaya

et al. 2019

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Do nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We addressed this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebuliser expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing.We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

Martins

Mazibuko

Zelaya

et al. 2019

Preprint

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“…Specifically OXT increased activation in the amygdala during unpredictable bottom-up aversive anticipation in low trait anxiety individuals. Several previous studies reported OXT attenuated anxiety by reducing amygdala reactivity in response to threatening social stimuli (Eckstein et al, 2015;Grace et al, 2018;Kanat et al, 2015;Spengler et al, 2017), which were primarily interpreted as anxiolytic effects of OXT. On the other hand some studies showed that OXT does not reduce but rather increases threat responses in humans and animals in some contexts (Grillon et al, 2013;Guzmán et al, 2013;Striepens et al, 2012), suggesting that OXT may produce anxiolytic versus anxiogenic effects depending on the specific context as well as individual factors (Bartz et al, 2011;Olff et al, 2013).…”

Section: Oxytocin Modulates Anticipatory Activation In the Posterior mentioning

confidence: 96%

“…The amygdala was chosen based on previous studies demonstrating OXT-induced attenuated amygdala threat reactivity (e.g. Spengler et al, 2017;Striepens et al, 2012). The amygdala mask was created using the AAL atlas (Tzourio-Mazoyer et al, 2002) implemented in WFU Pickatlas (Maldjian et al, 2003).…”

Section: Fmri Data Acquisitionmentioning

confidence: 99%

“…Previous animal models and human studies provided extensive evidence for an important role of the hypothalamic neuropeptide oxytocin (OXT) in anxiety, and based on these findings intranasal OXT has been suggested as potential promising pharmacological treatment for anxiety and fear-related disorders (Eckstein et al, 2015;Knobloch et al, 2012;Neumann and Slattery, 2016;Spengler et al, 2017). Converging evidence indicates an anxiolytic potential of intranasal OXT reflected by reduced amygdala responses but increased amygdala-prefrontal cortex (PFC) functional connectivity in response to threatening stimuli in healthy adults (Domes et al, 2007;Eckstein et al, 2015;Petrovic et al, 2008;Striepens et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Oxytocin differentially modulates amygdala responses during top-down and bottom-up aversive anticipation

Xin

Zhou

Dong

et al. 2020

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The ability to successfully regulate negative emotions such as fear and anxiety is vital for mental health.The neuropeptide oxytocin (OXT) acts as important modulator of emotion regulation, as reflected by reduced amygdala responses but increased amygdala-prefrontal cortex (PFC) functional connectivity in response to threatening stimuli. The present randomized, between-subject, placebo (PLC)controlled pharmacological study combined intranasal administration of OXT with functional MRI during an explicit (cognitive) emotion regulation (i.e. distancing reappraisal) paradigm in 65 healthy male participants to investigate the modulatory effects of OXT on both bottom-up and top-down emotion regulation. OXT attenuated the activation in posterior insular cortex and amygdala during anticipation of top-down regulation of predictable threat stimuli in participants with high trait anxiety, providing evidence to support the anxiolytic action of OXT. In contrast, OXT enhanced amygdala activity during bottom-up anticipation of an unpredictable threat stimulus in participants with low trait anxiety. OXT may thus facilitate top-down goal-directed attention by attenuating amygdala activity in high anxiety individuals, while promote bottom-up attention/vigilance to unexpected threat by enhancing anticipatory amygdala activity in low anxiety individuals. The opposite effects of OXT on anticipatory amygdala activation in high versus low anxiety individuals may suggest a baseline anxiety level dependent mechanism via which OXT promotes optimal levels of amygdala activation during the anticipation of an imminent threat. OXT may thus have the potential to promote an adaptive balance between bottom-up and top-down attention systems depending on individual levels of pre-treatment trait anxiety levels. 2017; Zilverstand et al., 2017). Behavioral interventions (Campbell-Sills and Barlow, 2007; Gross et al., 2006; Jazaieri et al., 2015), neurofeedback targeting the amygdala-prefrontal circuits (Cohen Kadosh et al., 2016; Zhao et al., 2019) and pharmacological agents primarily targeting serotonergic and GABAergic neurotransmission (Farach et al., 2012; Singewald et al., 2015) can facilitate the regulation of negative emotions, including anxiety and fear. However, not all patients respond adequately to the currently available treatment strategies and the pharmacological interventions may induce negative side-effects which often limit compliance with the treatment protocols, thus novel strategies to improve emotion regulation are urgently needed.Emotion generation and regulation involves the interaction of intrinsic/automatic bottom-up processes and controlled/deliberately top-down processes (Ochsner and Gross, 2005;Ochsner and Gross, 2007;Suri et al., 2013). Bottom-up processes are stimulus-driven and initiated by salient stimuli in the environment. In contrast, top-down processes are goal-driven and context-dependent (Beck and Kastner, 2009;Desimone and Duncan, 1995;Sussman et al., 2016a). During both the (pre-stimulus) anticipation and adven...

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Oxytocin Differentially Modulates Amygdala Responses during Top‐Down and Bottom‐Up Aversive Anticipation

et al. 2020

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The ability to successfully regulate negative emotions such as fear and anxiety is vital for mental health. Intranasal administration of the neuropeptide oxytocin (OXT) has been shown to reduce amygdala activity but to increase amygdala-prefrontal cortex connectivity during exposure to threatening stimuli suggesting that it may act as an important modulator of emotion regulation. The present randomized, between-subject, placebo-controlled pharmacological study combines the intranasal administration of OXT with functional magnetic resonance imaging (fMRI) during an explicit emotion regulation paradigm in 65 healthy male participants to investigate the modulatory effects of OXT on both bottom-up and top-down emotion regulation. OXT attenuates the activation in the posterior insular cortex and amygdala during anticipation of top-down regulation of predictable threat stimuli in participants with high trait anxiety. In contrast, OXT enhances amygdala activity during the bottom-up anticipation of unpredictable threat stimuli in participants with low trait anxiety. OXT may facilitate top-down goal-directed attention by attenuating amygdala activity in high anxiety individuals, while promoting bottom-up attention/vigilance to unexpected threats by enhancing amygdala activity in low anxiety individuals. OXT may thus have the potential to promote an adaptive balance between bottom-up and top-down attention systems depending on an individual's trait anxiety level.

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Kinetics and Dose Dependency of Intranasal Oxytocin Effects on Amygdala Reactivity

Cited by 214 publications

References 75 publications

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

Oxytocin differentially modulates amygdala responses during top-down and bottom-up aversive anticipation

Oxytocin Differentially Modulates Amygdala Responses during Top‐Down and Bottom‐Up Aversive Anticipation

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