A novel V1a receptor antagonist blocks vasopressin-induced changes in the CNS response to emotional stimuli: an fMRI study

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.

Effects of oxytocin and vasopressin on the neural response to unreciprocated cooperation within brain regions involved in stress and anxiety in men and women

“…On the other hand, weak AVP binding has been reported in the dorsolateral part of the basal amygdaloid nucleus(Loup et al 1991), raising the possibility that any AVP effects in the amygdala are due to its binding to its own receptor. Finally, these marginal effects of AVP could be related to dosage, since some published studies showing significant effects of AVP on brain activity use 40 IU (rather than 20 IU as used here) (Lee et al 2013; Zink et al 2011). In women, 20 IU intranasal AVP had no effect in either the anterior insula or the amygdala with either human or computer partners.…”

Sex differences in the hypothalamic–pituitary–adrenal axis: An obstacle to antidepressant drug development?

“…Unfortunately, these studies did not compare data by sex. In healthy subjects, sex has been examined, and plasma AVP levels were positively correlated with distress in a pair‐bonded relationship in men, but not in women (Taylor, Saphire‐Bernstein, & Seeman, ) and recently it was shown that V 1A antagonists attenuated amygdala activation in response to aversive stimuli only in male subjects (Lee et al, ).…”

Inhibition of vasopressin V1a receptors in the medioventral bed nucleus of the stria terminalis has sex- and context-specific anxiogenic effects

“…Acute pharmacological inhibition of V1aRs can produce anxiolytic effects while genetic deletion of V1aR produced both anxiolytic effects and reductions in social function in male mice (Bielsky et al, 2004). The modulation of both social behavior and anxiety by V1aR has sparked interest in its potential as a novel therapeutic target for stress-related psychiatric disorders, in which anxiety and social deficits can be comorbid (Lee et al, 2013; Meyer-Lindenberg and Tost, 2012). Currently it is unclear whether the effects of V1aR on social and anxiety-like behavior are mediated by independent or overlapping circuits.…”