Oxytocin and Fear Memory Extinction: Possible Implications for the Therapy of Fear Disorders?

Barbara Rani,Maria Beatrice Passani,Alessia Costa,Elisabetta Baldi,Adele Romano,Gustavo Provensi,Patrizio Blandina

doi:10.3390/ijms221810000

Barbara Rani, Maria Beatrice Passani + Show 5 more

Open Access

https://doi.org/10.3390/ijms221810000

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Abstract

Several psychiatric conditions such as phobias, generalized anxiety, and post-traumatic stress disorder (PTSD) are characterized by pathological fear and anxiety. The main therapeutic approach used in the management of these disorders is exposure-based therapy, which is conceptually based upon fear extinction with the formation of a new safe memory association, allowing the reduction in behavioral conditioned fear responses. Nevertheless, this approach is only partially resolutive, since many patients have difficulty following the demanding and long process, and relapses are frequently observed over time. One strategy to improve the efficacy of the cognitive therapy is the combination with pharmacological agents. Therefore, the identification of compounds able to strengthen the formation and persistence of the inhibitory associations is a key goal. Recently, growing interest has been aroused by the neuropeptide oxytocin (OXT), which has been shown to have anxiolytic effects. Furthermore, OXT receptors and binding sites have been found in the critical brain structures involved in fear extinction. In this review, the recent literature addressing the complex effects of OXT on fear extinction at preclinical and clinical levels is discussed. These studies suggest that the OXT roles in fear behavior are due to its local effects in several brain regions, most notably, distinct amygdaloid regions.

Highlights

Pathological fear and anxiety are a hallmark of many psychiatric conditions, such as phobias, generalized anxiety, and post-traumatic stress disorder (PTSD)
Experimental results have shown that medial prefrontal cortex (mPFC) is able to exert a dual control over fear expression through separate pathways, each with access to separate sets of inputs and outputs [116]
Whereas PL is involved in the production of fear responses and its inactivation reduces expression of contextual and auditory fear conditioning [86,117], IL is a critical site of plasticity for the inhibition of fear responses and, for the extinction

Summary

Introduction

Pathological fear and anxiety are a hallmark of many psychiatric conditions, such as phobias, generalized anxiety, and post-traumatic stress disorder (PTSD). Since various subgroups of OXT neurons may innervate distinct brain regions [45], it can be hypothesized that certain stimuli selectively activate neuronal populations with specific intracerebral projections It was recently shown by genetic labeling of OXT neurons activated during fear expression in rats that these “fear-sensitive” OXT cells almost exclusively project to the central nucleus of amygdala, one of the major regions of fear response [46]. The multiple and known effects of OXT, including its role in controlling stress, anxiety [59,60,61], and modulating fear responses [46,62,63], suggest OXT as an attractive treatment option in human diseases associated with socio-emotional dysfunctions, such as PTSD, generalized anxiety, phobias, and major depressive disorders. Further research is needed to establish OXT as a safe treatment option

Fear Memory Extinction and Underpinning Network

Oxytocin Effects on Fear Memory Extinction

Preclinical Studies

Human Studies

Challenges and Perspectives on OXT Research and Therapeutic Exploitation