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

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.

Oxytocin enhances the pain-relieving effects of social support in romantic couples.

Social support plays a vital role in physical and mental well-being. The neuropeptide hormone oxytocin (OXT) has been implicated in modulating pair-bonding and affiliative behaviors, but whether OXT contributes to the analgesic effects of a romantic partner's touch remains elusive. In the present randomized placebo-controlled, between-group, functional magnetic resonance imaging study involving 194 healthy volunteers (97 heterosexual couples), we tested the effects of intranasal OXT (24 IU) on handholding as a common mode of expressing emotional support in romantic couples. We scanned the subjects while brief electric shocks were administered. The subjects assumed that they received social support from either their romantic partner or an unfamiliar person. Unbeknown to the subject, in the partner and stranger support conditions, the same male experimenter always held the subject's left hand. Partner support was most effective in reducing the unpleasantness of electric shocks, and OXT further attenuated the unpleasantness across conditions. On the neural level, OXT significantly augmented the beneficial effects of partner support, as evidenced by a stronger decrease of neural responses to shocks in the anterior insula (AI), a stronger activity increase in the middle frontal gyrus (MFG), and a strengthened functional coupling between the AI and MFG. Our results support the notion that OXT specifically modulates the beneficial effects of social support in romantic couples by concomitantly reducing pain-associated activity and increasing activity linked to cognitive control and pain inhibition. We hypothesize that impaired OXT signaling may contribute to the experience of a lack of partner support.

Oxytocin for learning calm and safety.

The appropriate discrimination between safe and dangerous situations and the subsequent decrease of fear expression in the presence of safety signals are crucial for survival and mental health. Learning of safety associations is often studied in terms of fear extinction, that is re-learning of a previously conditioned stimulus which is now no longer positively associated with danger. Numerous studies investigated neurobiological processes of fear extinction and provide a valid picture of the underlying neural structures and endocrine processes involved. However, a formerly neutral conditioned stimulus (CS) can also predict the non-occurrence of an aversive, potentially dangerous, unconditioned stimulus (US) from the very beginning and thus can serve as a safety stimulus. This process has been termed safety learning. Although safety learning has been known for almost a century, there has been little research on its underlying neurobiological mechanisms, in contrast to the more prominent Pavlovian fear conditioning and fear extinction. In this review, we propose that the well-known action of the hypothalamic neuropeptide oxytocin (OXT) in the regulation of fear and stress responses is complementary to safety learning. We summarize the literature focused on OXT signaling and safety learning in animals and humans, from the first studies of fear extinction and conditioned inhibition of fear to the most recent findings in molecular and behavioral research on initial social safety stimuli. At the end, we discuss the application of OXT as a therapeutic agent to psychopathologies related to deficits in safety learning.

How the brain codes intimacy: The neurobiological substrates of romantic touch.

Humans belong to a minority of mammalian species that exhibit monogamous pair-bonds, thereby enabling biparental care of offspring. The high reward value of interpersonal closeness and touch in couples is a key proximate mechanism facilitating the maintenance of enduring romantic bonds. However, surprisingly, the neurobiological underpinnings mediating the unique experience of a romantic partner's touch remain unknown. In this randomized placebo (PLC)-controlled, between-group, pharmacofunctional magnetic resonance imaging (fMRI) study involving 192 healthy volunteers (96 heterosexual couples), we intranasally administered 24 IU of the hypothalamic peptide oxytocin (OXT) to either the man or the woman. Subsequently, we scanned the subjects while they assumed that they were being touched by their romantic partners or by an unfamiliar person of the opposite sex, although in reality an identical pattern of touch was always given by the same experimenter. Our results show that intranasal OXT compared to PLC selectively enhanced the subjective pleasantness of the partner's touch. Importantly, intranasal OXT selectively increased responses to partner touch in the nucleus accumbens (NAcc) and anterior cingulate cortex. Under OXT, NAcc activations to partner touch positively correlated with the subjects' evaluation of their relationship quality. Collectively, our results suggest that OXT may contribute to the maintenance of monogamous relationships in humans by concomitantly increasing the reward value of partner touch and diminishing the hedonic quality of stranger touch. Hum Brain Mapp 38:4525-4534, 2017. © 2017 Wiley Periodicals, Inc.