Abstract
Background: We hypothesized that SRX246, a vasopressin V1a receptor antagonist, blocks the effect of intranasally administered vasopressin on brain processing of angry Ekman faces. An interaction of intranasal and oral drug was predicted in the amygdala.Methods: Twenty-nine healthy male subjects received a baseline fMRI scan while they viewed angry faces and then were randomized to receive oral SRX246 (120 mg PO twice a day) or placebo. After an average of 7 days of treatment, they were given an acute dose of intranasal vasopressin (40 IU) or placebo and underwent a second scan. The primary outcome was BOLD activity in the amygdala in response to angry faces. Secondary analyses were focused on ROIs in a brain regions previously linked to vasopressin signaling.Results: In subjects randomized to oral placebo-intranasal vasopressin, there was a significantly diminished amygdala BOLD response from the baseline to post-drug scan compared with oral placebo-intranasal placebo subjects. RM-ANOVA of the BOLD signal changes in the amygdala revealed a significant oral drug × intranasal drug × session interaction (F(1, 25) = 4.353, p < 0.05). Follow-up tests showed that antagonism of AVPR1a with SRX246 blocked the effect of intranasal vasopressin on the neural response to angry faces. Secondary analyses revealed that SRX246 treatment was associated with significantly attenuated BOLD responses to angry faces in the right temporoparietal junction, precuneus, anterior cingulate, and putamen. Exploratory analyses revealed that the interactive and main effects of intranasal vasopressin and SRX246 were not seen for happy or neutral faces, but were detected for aversive faces (fear + anger) and at a trend level for fear faces.Conclusion: We found confirmatory evidence that SRX246 has effects on the amygdala that counter the effects of intranasal vasopressin. These effects were strongest for angry faces, but may generalize to other emotions with an aversive quality.
Highlights
Vasopressin (AVP) is a mediator of social and emotional behavior in many species (Garrison et al, 2012) including humans, and it has been suggested that arginine vasopressin (AVP) receptor antagonists might be useful for treating stress-related neuropsychiatric problems including inappropriate aggression, post-traumatic stress disorder, and major depression (Meyer-Lindenberg and Tost, 2012)
In subjects randomized to oral placebo-intranasal vasopressin, there was a significantly diminished amygdala blood oxygen level dependent (BOLD) response from the baseline to post-drug scan compared with oral placebo-intranasal placebo subjects
Follow-up tests showed that antagonism of AVPR1a with SRX246 blocked the effect of intranasal vasopressin on the neural response to angry faces
Summary
Vasopressin (AVP) is a mediator of social and emotional behavior in many species (Garrison et al, 2012) including humans, and it has been suggested that AVP receptor antagonists might be useful for treating stress-related neuropsychiatric problems including inappropriate aggression, post-traumatic stress disorder, and major depression (Meyer-Lindenberg and Tost, 2012). The V1a receptor is the dominant CNS subtype and is found throughout the limbic system and several cortical regions, providing a strong rationale for determining the potential role of this receptor in the regulation of emotion To this end, SRX246 was developed as a novel, AVPR1a antagonist that penetrates the blood brain barrier and has CNS effects in multiple preclinical models (Ferris et al, 2008; Simon et al, 2008; Fabio et al, 2013). An interaction of intranasal and oral drug was predicted in the amygdala
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