Common and dissociable effects of oxytocin and lorazepam on the neurocircuitry of fear

Abstract

<jats:p>Benzodiazepines (BZDs) represent the gold standard of anxiolytic pharmacotherapy; however, their clinical benefit is limited by side effects and addictive potential. Consequently, there is an urgent need to develop novel and safe anxiolytics. The peptide hormone oxytocin (OXT) exhibits anxiolytic-like properties in animals and humans, but whether OXT and BZDs share similar effects on the neural circuitry of fear is unclear. Therefore, the rationale of this ultra-high-field functional MRI (fMRI) study was to test OXT against the clinical comparator lorazepam (LZP) with regard to their neuromodulatory effects on local and network responses to fear-related stimuli. One hundred twenty-eight healthy male participants volunteered in this randomized double-blind, placebo-controlled, between-group study. Before scanning using an emotional face-matching paradigm, participants were randomly administered a single dose of OXT (24 IU), LZP (1 mg), or placebo. On the behavioral level, LZP, but not OXT, caused mild sedation, as evidenced by a 19% increase in reaction times. On the neural level, both OXT and LZP inhibited responses to fearful faces vs. neutral faces within the centromedial amygdala (cmA). In contrast, they had different effects on intra-amygdalar connectivity; OXT strengthened the coupling between the cmA and basolateral amygdala, whereas LZP increased the interplay between the cmA and superficial amygdala. Furthermore, OXT, but not LZP, enhanced the coupling between the cmA and the precuneus and dorsomedial prefrontal cortex. These data implicate inhibition of the cmA as a common denominator of anxiolytic action, with only OXT inducing large-scale connectivity changes of potential therapeutic relevance.</jats:p>

“Less is more”: a dose-response account of intranasal oxytocin pharmacodynamics in the human brain

“…The independent modulation of physiology (rCBF) in amygdala's subdivisions by a single dose of intranasal oxytocin, compared to placebo, that we observed in this study is corroborated by previous studies using BOLD-fMRI 48,59,60 . Here, we extend these previous findings by using a physiological quantitative neuroimaging biomarker that can be more closely linked to changes in neural activity and captures the intrinsic regional response of the amygdala circuits to intranasal oxytocin in the absence of a specific psychological manipulations.…”

Oxytocin Promotes Accurate Fear Discrimination and Adaptive Defensive Behaviors

“…Based on the widespread OTR expression and brain region-specific role of OT, caution needs to be applied when interpreting results based on ICV, and especially based on systemic or intranasal OT administration. Although OT administered intranasally has been shown to modulate amygdala activity in humans ( Kreuder et al, 2020 ) and increase OT levels in the amygdala in rodents ( Neumann et al, 2013 ), other brain regions might also be involved in the behavioral OT effects.…”

Oxytocinergic modulation of threat-specific amygdala sensitization in humans is critically mediated by serotonergic mechanisms

“…Gao et al, 2016) only male participants were included. Given the complexity of the design, a pragmatic approach for sample size determination was employed based on a recent fMRI study (23) comparing effects of different OXT dosages on threat-related amygdala activity (for a similar approach see recent study comparing OXT with another anxiolytic agent) (24). Exclusion criteria included: (1) current/history of physical or psychiatric disorders, (2) current/regular use of licit or illicit psychotropic substances, (3) weight >85 kilograms, (4) MRI contraindications, (5) cardiovascular disorders including high blood pressure, (6) contraindications for either OXT or acute tryptophan depletion (ATD) protocol.…”