The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin. In humans, the oxytocin receptor is encoded by the OXTR gene which has been localized to human chromosome 3p25.
The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin. In humans, the oxytocin receptor is encoded by the OXTR gene which has been localized to human chromosome 3p25.
The OXTR protein belongs to the G protein-coupled receptor (GPCR) family, specifically Gq, and acts as a receptor for oxytocin. Its activity is mediated by G proteins that activate several different second messenger systems.
Oxytocin receptors are expressed by the myoepithelial cells of the mammary gland, and in both the myometrium and endometrium of the uterus at the end of pregnancy. The oxytocin receptor system plays an important role as an inducer of uterine contractions during parturition and of milk ejection.
OXTR is also associated with the central nervous system. The gene is believed to play a major role in social, cognitive, and emotional behavior. A decrease in OXTR expression by methylation of the OXTR gene is associated with callous and unemotional traits in adolescence, rigid thinking in anorexia nervosa, problems with facial and emotional recognition, and difficulties in the affect regulation. A reduction in this gene is believed to lead to prenatal stress, postnatal depression, and social anxiety. Studies on OXTR methylation—which downregulates oxytocin mechanisms—suggest this process is associated with increased gray matter density in the amygdala, implicating OXTR regulation in stress and parasympathetic regulation.
Social isolation has been found to decrease oxytocin receptor levels in rodents, whereas levels of oxytocin were unchanged. The decreased oxytocin receptor levels were associated with behavioral changes including increased aggression and anxiety-like behavior, hyperactivity, and diminished social behaviors and memory. Exogenous administration of oxytocin receptor agonists like oxytocin or TGOT was able to partially reverse the behavioral changes.
Fecal microbiota transplant from people with social anxiety disorder into rodents caused selective social anxiety-like symptoms in the rodents. This was associated with brain oxytocinergic abnormalities, including decreased expression of the oxytocin receptor. Lactobacillus reuteri has been found to increase oxytocinergic signaling in rodents, with its metabolite ergothioneine reducing social avoidance behavior. Conversely, propionic acid (propionate), which is produced by certain gut bacteria and is increased by social isolation, has been found to induce social deficits and anxiety in rodents, with this being associated with decreased oxytocin receptor expression.
In some mammals, oxytocin receptors are also found in the kidney and heart.
The oxytocinergic circuit projecting from the paraventricular hypothalamic nucleus (PVN) innervates the ventral tegmental area (VTA) dopaminergic neurons that project to the nucleus accumbens, i.e., the mesolimbic pathway. Activation of the PVN→VTA projection by oxytocin affects sexual, social, and addictive behavior via this link to the mesolimbic pathway; specifically, oxytocin exerts a prosexual and prosocial effect in this region.
The receptors for oxytocin (OXTR) have genetic differences with varied effects on individual behavior. The polymorphism (rs53576) occurs on the third intron of OXTR in three types: GG, AG, AA. The GG allele is connected with oxytocin levels in humans.[citation needed] A-allele carriers are associated with more sensitivity to stress, lower social proficiency, and more mental health issues than the GG carriers.[qualify evidence]
In a study looking at empathy and stress, individuals with the allele GG scored higher than A-carrier individuals in a "Reading the Mind in the Eyes" test. GG carriers, with their naturally higher levels of oxytocin, were better able to distinguish between emotions.[citation needed] A-allele carriers responded with more stress to stressful situations than GG-allele carriers.[further explanation needed] A-allele carriers had lower scores on psychological resources, like optimism, mastery, and self-esteem, than GG individuals when measured with factor analysis for depressive symptomology and psychological resources, along with the Beck Depression Inventory. A-allele carriers had higher depressive symptomology and lower psychological resources than GG individuals.[qualify evidence] A-allele individuals scored lower in human sociality than GG people on a Tridimensional Personality Questionnaire. AA individuals had the lowest amygdala activation while processing emotionally salient information and those with GG had the highest activity when tested using BOLD during an fMRI. On the other hand, variations at the CD38 rs3796863 and OXTR rs53576 loci were not associated with psychosocial characteristics of adolescents assessed with the Strengths and Difficulties Questionnaire (SDQ); in studies with a similar design, authors recommend replication with larger samples and greater power to detect small effects, especially in age–sex subgroups of adolescents.
The frequency of the A allele varies among ethnic groups, being significantly more common among East Asians than Europeans.[quantify][additional citation(s) needed]
Some evidence suggests an association between OXTR gene polymorphism, IQ, and autism spectrum disorder (ASD). Studies have done research focusing on variants in the third intron of the gene, a region that is strongly correlated with personality traits and ASD. OXTR knockout mice have shown abnormal behaviors such as social impairments and aggressiveness. These abnormalities can be reduced with oxytocin or oxytocin receptor agonist administration. Overall, the study suggests that rare variants are considerably more abundant in individuals with ASD compared to that of healthy individuals, however further research with larger sample sizes is needed.
Several selective ligands for the oxytocin receptor have been developed, but close similarity between the oxytocin and related vasopressin receptors make it difficult to achieve high selectivity with peptide derivatives. However the search for a druggable, non-peptide template has led to several potent, highly selective, orally bioavailable oxytocin receptor antagonists. Oxytocin receptor agonists have also been developed.
In order to test the hypothesis that the microbiota plays a causal role in SAD, we subsequently used faecal microbiota transplantation (FMT), a method used to assess potential causality and mechanisms [52, 53]. This involved the transfer of the microbiota from patients with SAD to antibioticdepleted mice recipients and assessment of the behavioural and biological impact of such microbiota alteration [54]. Interestingly, the mice who received the SAD microbiome demonstrated a specific heightened social fear response, a validated mouse model of SAD [55]. They performed normally across other tests evaluating general anxiety-like and depression-like behaviours, an important feature of the study highlighting specificity for social fear responses. Additionally, changes in central and peripheral immune function and oxytocin expression in the bed nucleus of the stria terminalis were evident in the SAD-FMT-recipient mice.
FMT from individuals with SAD into mice revealed that gut microbiota can induce heightened sensitivity to social fear, mirroring symptoms of SAD.70 This response was accompanied by notable changes in both central and peripheral immune functions and a reduction in oxytocin expression within the bed nucleus of the stria terminalis.
Microbiome transfers from adult humans with social anxiety disorder into mice increases sensitivity to social fear compared with microbiome transfers from healthy control individuals39. The fact that microbiome composition is sufficient to modulate social stress responses, at least in rodent models, suggests that targeted microbial interventions might be a feasible approach to reduce the negative outcomes of stress. [...] In a mouse model where mothers are fed a high-fat diet (MHFD), offspring exhibit social deficits and an altered microbiome with reduced diversity and decreased abundance of beneficial microorganisms from the Lactobacillus and Bifidobacterium genera58. Treatment with Lactobacillus reuteri upregulates oxytocinergic neurons in the paraventricular nucleus of the hypothalamus and rescues altered social behaviour in offspring of MHFD dams and several ASD models via vagus nerve signalling (Fig. 1) and/or the involvement of ventral tegmental area dopaminergic neurons57–59
[...] multiple preclinical studies demonstrate that propionic acid is a potential neurotoxin. Propionic acid can cross the blood-brain barrier and induce inflammation, oxidative stress, mitochondrial dysfunction, while influencing and neurotransmission and gene expression.3 Indeed, propionic acid has been linked to increased anxiety and impairments in typical social behavior among animals.4,5
[...] juvenile social isolation decreases the expression of oxytocin receptor (OXTR) in the medial prefrontal cortex (mPFC), and increases the amounts of fecal propionic acid (PA), a short-chain fatty acid derived from gut micobiota. Accordingly, infusion with an OXTR antagonist (OXTR-A, l-368,899) specifically in the mPFC or supplementation of PA both can cause social deficits and anxiety-like behaviors in group housed mice. Collectively, our findings reveal that juvenile social experience regulates prefrontal cortical OXTR expression through gut microbiota-produced PA and that is essential for normal social and emotional behaviors, [...]
Recent studies also highlight remarkable anxiolytic and prosocial effects of intranasally administered OT in humans, including increased 'trust', decreased amygdala activation towards fear-inducing stimuli, improved recognition of social cues and increased gaze directed towards the eye regions of others (Kirsch et al., 2005; Kosfeld et al., 2005; Domes et al., 2006; Guastella et al., 2008).
Kinoxis' lead candidate (KNX100) is being developed for the mitigation of opioid withdrawal symptoms. KNX100 has a novel, undisclosed mechanism of action and a Phase I clinical trial has commenced under a US IND. The company is also exploring other indications for its lead compound, KNX100, as promising preclinical results have been achieved in animal models of cocaine, methamphetamine, nicotine, and alcohol use disorders, as well as models of agitation and aggression. [...] Kinoxis' second series of compounds target the oxytocin receptor, through either selective partial agonism or positive allosteric modulation. The brain oxytocin system has been identified as perhaps the most important molecular target for regulating social behaviour and is therefore a major target of interest for treating a wide range of mental disorders. The development of these compounds will be focused on treating conditions that feature social dysfunction as a core symptom, such as neurodevelopmental disorders (including autism spectrum disorder), social anxiety disorder, dementia (including Alzheimer's disease), PTSD and schizophrenia. The KNX200 series of oxytocin receptor partial agonists are undergoing candidate selection stage using several pre-clinical animal disease models (Alzheimer's, PTSD, ASD) and the KNX300/400 series of oxytocin receptor positive allosteric modulators are undergoing lead optimisation.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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