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

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.

Roles of Oxytocin in Stress Responses, Allostasis and Resilience

“…Oxytocin regulates stress responses in the neuroendocrine system, autonomic nervous system, immune system and behaviors. In many studies using both animal and human subjects, oxytocin has been shown to reduce the activity of the hypothalamic-pituitary-adrenal (HPA) axis [ 55 , 56 , 57 , 58 , 59 , 60 ], regulate autonomic stress responses [ 19 , 61 , 62 , 63 , 64 ], attenuate inflammation [ 65 , 66 , 67 ] and reduce anxiety-related behaviors [ 23 , 24 , 68 , 69 , 70 ]. Oxytocin-deficient female mice, but not oxytocin-deficient male mice, have been reported to show increased anxiety-related behaviors in an elevated plus maze test [ 71 ].…”

“…This phenomenon has been reported to be mediated by activation of oxytocin receptor-expressing GABAergic neurons in the lateral part of the CeA that inhibit neurons in the medial part of the CeA projecting to the periaqueductal gray [ 127 ]. However, mixed and contradictory data concerning the effects of oxytocin on fear conditioning in the basolateral amygdala and the CeA have also been reported (Please see other reviews for details [ 24 , 69 ]).…”

Toxoplasma gondii Infection Causes an Atypical Abundance of Oxytocin and Its Receptor in the Female Rat Brain

“…Additionally, fear extinction in both humans and rodents requires complex interactions between several brain regions and the OT-OTR system. This suggests that while the data presented in this paper focus on OT and OTR expression in the medial amygdala and the hypothalamus, other brain regions that are not primarily involved in fear behavior, including the hippocampus and medial prefrontal complex, may also play a role in the loss of aversion to bobcat odor observed after chronic Toxoplasma infection, and warrant investigation to determine whether they play a role in Toxoplasma-mediated behavior change [15].…”

Hallucinogenic drugs and their potential for treating fear‐related disorders: Through the lens of fear extinction

“…Amygdala is a complex of nuclei, with basolateral (BLA) nuclei and central amygdala (CeA)—divided into lateral (CeL) and medial (CeM) subregions—being crucially involved in the acquisition and extinction of conditioned fear responses. While the CeM drives the expression of fear, BLA is involved both in the acquisition and extinction of fear, due to the presence of two distinct neuronal subpopulations: “fear neurons” and “extinction neurons” (Baldi et al, 2021). While “fear neurons” show increased firing rate during fear conditioning and fear memory retention, “extinction neurons” are activated during extinction training and recall of extinction memory (Baldi et al, 2021).…”

“…While the CeM drives the expression of fear, BLA is involved both in the acquisition and extinction of fear, due to the presence of two distinct neuronal subpopulations: “fear neurons” and “extinction neurons” (Baldi et al, 2021). While “fear neurons” show increased firing rate during fear conditioning and fear memory retention, “extinction neurons” are activated during extinction training and recall of extinction memory (Baldi et al, 2021). Therefore, a subpopulation of BLA neurons is crucial for extinction acquisition and storage of extinction memory (Baldi et al, 2021; Milad & Quirk, 2012).…”