Wednesday, June 03, 2020

Anxiolytic actions of oxytocin, unlike those of benzodiazepines, involve brain regions outside the amygdala


A potential new target for anxiolytic drug development is the oxytocin (OXT) neuropeptide system. An emerging question is whether OXT has similar effects on the neural microcircuitry of fear compared with clinically established compounds such as benzodiazepines. The present functional MRI study showed that both OXT and its benzodiazepine comparator lorazepam (LZP) reduced centromedial amygdala responses to fear signals. OXT, but not LZP, increased extra-amygdalar connectivity between the centromedial amygdala and frontoparietal regions. Thus, while both compounds inhibited the centromedial amygdala, OXT, but not LZP, elicited large-scale connectivity changes of potential therapeutic relevance.


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.

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