Oxytocin in General Anxiety and Social Fear: A Translational Approach

Abstract

The neuropeptide oxytocin (OXT) has been revealed as a profound anxiolytic and antistress factor of the brain, besides its many prosocial and reproductive effects. Therefore, there is substantial scientific and medical interest in its potential therapeutic use for the treatment of psychopathologies associated with anxiety, fear, and social dysfunctions, such as generalized anxiety disorder, posttraumatic stress disorder, and social anxiety disorder, as well as autism and schizophrenia, among others. Focusing on preclinical studies, we review the existing evidence for the regulatory capacity of OXT to fine-tune general and social anxiety-related behaviors, as well as cued and social fear conditioning from a translational perspective. The available evidence from animal and human studies substantiates the hypothesis of an imbalance of the endogenous brain OXT system in the etiology of anxiety disorders, particularly those with a social component such as social anxiety disorder. In addition, such an imbalance of the OXT system is also likely to be the consequence of chronic OXT treatment resulting in a dose-dependent reduction in OXT receptor availability and increased anxiety.

The potential of oxytocin as a therapeutic target for psychiatric disorders

“…In clinical trials, there is some evidence for positive effects of OXT via this non-invasive route of treatment on various aspects of social behavior (empathy, face recognition and verbal memory) in autistic, schizophrenic or social anxiety patients. [1,16] In Fragile X patients, who also display symptoms of social anxiety, intranasal OXT improved eye gazing and reduced cortisol responses to a social challenge. [1] These studies generally emphasize OXT as a very interesting add-on therapy for various psychiatric diseases, especially those characterized by emotional and/or social dysfunctions.…”

“…[1,16] In Fragile X patients, who also display symptoms of social anxiety, intranasal OXT improved eye gazing and reduced cortisol responses to a social challenge. [1] These studies generally emphasize OXT as a very interesting add-on therapy for various psychiatric diseases, especially those characterized by emotional and/or social dysfunctions. However, we currently face various challenges in order to establish OXT as a safe treatment option, also over longer periods of time.…”

“…Moreover, OXT mediates the positive consequences of social support and reverses social fear in social fear-conditioned mice. [1] In addition to its multiple pro-social effects, it also reduces aggression, anxiety-related behavior and the stress response (for review see [1,2]). The OXT system also emerges as an important regulator of drug addiction: in rodents, it attenuates tolerance to and decreases withdrawal symptoms of opioids, inhibits the rewarding effect of psychostimulants like methamphetamine and cocaine, and reduces alcohol consumption while attenuating ethanolinduced sedation and ataxia.…”

“…[5] Epigenetic modifications, particularly the degree of methylation of CpG dinucleotides, were associated with the formation of a specific behavioral phenotype: decreased OXTR methylation, and with that postulated increased OXTR expression, was associated with the categorical phenotype of SAD with traits related to social anxiety, increased cortisol response to a stressor and increased amygdala activation. [1,6] However, none of these studies has ever linked the genetic variations in the OXTR gene with functional consequences and, therefore, it remains unknown whether reduced or increased OXTR functionality can be expected, for example, in A allele carriers.…”

Noxious or Non-noxious Inputs to Oxytocin Neurons: Possible Roles in the Control of Behaviors

“…Oxytocin has also been reported to have various actions in mammals [24,50,56,65], including human-dog bonding [48], anxiolytic effects [49,79], modulation of stress-induced activation of the hypothalamo-pituitary-adrenal axis [20,30,62], modulation of (emotional) memory [45], induction of analgesia [25], termination of food intake [77], suppression of salt appetite [66], an increase in energy consumption [6,67], control of body temperature [33], antiinflammatory actions [11], facilitation of wound healing [26,73], restoration of ovariectomy-induced osteoporosis or obesity [12], protection of cardiomyocytes [28], recovery of age-dependent muscle mass decline [19], protective actions on neuronal damage [71], and control of neuronal development [35,82].…”