OXTR is also associated with the central nervous system. The gene is believed to play a major role in social, cognitive, and emotional behavior.[12] A decrease in OXTR expression by methylation of theOXTR gene is associated withcallous and unemotional traits in adolescence, rigid thinking inanorexia nervosa, problems with facial and emotional recognition, and difficulties in theaffect regulation. A reduction in this gene is believed to lead to prenatal stress, postnatal depression, and social anxiety.[12] Further research must be gathered before concluding these findings, however strong evidence is pointing in this direction. Studies onOXTR methylation—which downregulates oxytocin mechanisms—suggest this process is associated with increased gray matter density in the amygdala, implicatingOXTR regulation in stress and parasympathetic regulation.[13]
In some mammals, oxytocin receptors are also found in thekidney andheart.
The oxytocinergic circuit projecting from theparaventricular hypothalamic nucleus (PVN) innervates theventral tegmental area (VTA) dopaminergic neurons that project to thenucleus accumbens, i.e., themesolimbic pathway.[14] Activation of the PVN→VTA projection by oxytocin affects sexual, social, and addictive behavior via this link to the mesolimbic pathway;[14] specifically, oxytocin exerts a prosexual and prosocial effect in this region.[14]
The receptors for oxytocin (OXTR) have genetic differences with varied effects on individual behavior. Thepolymorphism (rs53576) occurs on the thirdintron of OXTR in three types: GG, AG, AA. The GG allele is connected with oxytocin levels in people[citation needed]. A-allele carrier individuals are associated with more sensitivity to stress, fewer social skills, and more mental health issues than the GG-carriers.[15][qualify evidence]
In a study looking atempathy andstress, 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.[16][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 theBeck Depression Inventory. A-allele carriers had higher depressive symptomology and lower psychological resources than GG individuals.[15][qualify evidence] A-allele individuals scored lower in human sociality than GG people on aTridimensional 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 anfMRI.[17] On the other hand, variations at the CD38 rs3796863 and OXTR rs53576 loci were not associated with psychosocial characteristics of adolescents assessed with theStrengths 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.[18]
The frequency of the A allele varies among ethnic groups, being significantly more common among East Asians than Europeans.[19][quantify][additional citation(s) needed]
Some evidence suggests an association between OXTR gene polymorphism,IQ, andautism spectrum disorder (ASD).[20] 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 agonist administration. Overall, the study suggests that rare variants are considerably more abundant in individuals with ASD compared to that of a normal individual, however further research with larger sample sizes must be completed before concluding any information.[21]
Several selectiveligands for the oxytocin receptor have recently been developed, but close similarity between the oxytocin and relatedvasopressin receptors make it difficult to achieve high selectivity with peptide derivatives.[22][23] However the search for a druggable, non-peptide template has led to several potent, highly selective, orally bioavailable oxytocin antagonists.[24]Oxytocin receptor agonists have also been developed.[25][26]
^Simmons CF, Clancy TE, Quan R, Knoll JH (April 1995). "The oxytocin receptor gene (OXTR) localizes to human chromosome 3p25 by fluorescence in situ hybridization and PCR analysis of somatic cell hybrids".Genomics.26 (3):623–5.doi:10.1016/0888-7543(95)80188-R.PMID7607693.
^Gimpl G, Reitz J, Brauer S, Trossen C (2008). "Oxytocin receptors: ligand binding, signalling and cholesterol dependence".Advances in Vasopressin and Oxytocin — from Genes to Behaviour to Disease. Progress in Brain Research. Vol. 170. pp. 193–204.doi:10.1016/S0079-6123(08)00417-2.ISBN978-0-444-53201-5.PMID18655883.
^Lerer, E., Levi, S., Salomon, S. et al. Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition. Mol Psychiatry 13, 980–988 (2008).https://doi.org/10.1038/sj.mp.4002087
^de Oliveira Pereira Ribeiro L, Vargas-Pinilla P, Kappel DB, Longo D, Ranzan J, Becker MM, et al. (June 2018). "Evidence for Association Between OXTR Gene and ASD Clinical Phenotypes".Journal of Molecular Neuroscience.65 (2):213–221.doi:10.1007/s12031-018-1088-0.PMID29858823.S2CID46924606.
^Chini B, Manning M (August 2007). "Agonist selectivity in the oxytocin/vasopressin receptor family: new insights and challenges".Biochemical Society Transactions.35 (Pt 4):737–41.doi:10.1042/BST0350737.PMID17635137.
^abManning M, Stoev S, Chini B, Durroux T, Mouillac B, Guillon G (2008). "Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: Research tools and potential therapeutic agents☆".Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Progress in Brain Research. Vol. 170. pp. 473–512.doi:10.1016/S0079-6123(08)00437-8.ISBN978-0-444-53201-5.PMID18655903.
^Borthwick AD (September 2010). "Oral oxytocin antagonists".Journal of Medicinal Chemistry.53 (18):6525–38.doi:10.1021/jm901812z.PMID20550119.
^Rahman Z, Resnick L, Rosenzweig-Lipson SJ, Ring RH,"Methods of treatment using oxytocin receptor agonists",US patent application 2007/0117794, published 2007-05-24 , assigned to Wyeth Corp
^Ring RH, Schechter LE, Leonard SK,Dwyer JM, Platt BJ, Graf R, et al. (January 2010). "Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist".Neuropharmacology.58 (1):69–77.doi:10.1016/j.neuropharm.2009.07.016.PMID19615387.S2CID8592340.
^abBorthwick AD, Liddle J (January 2013). "Retosiban and Epelsiban: Potent and Selective Orally available Oxytocin Antagonists". In Domling A (ed.).Methods and Principles in Medicinal Chemistry: Protein-Protein Interactions in Drug Discovery. Weinheim: Wiley-VCH. pp. 225–256.doi:10.1002/9783527648207.ch10.ISBN978-3-527-33107-9.
^Williams PD, Anderson PS, Ball RG, Bock MG, Carroll L, Chiu SH, et al. (March 1994). "1-((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo [2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperaz ine (L-368,899): an orally bioavailable, non-peptide oxytocin antagonist with potential utility for managing preterm labor".Journal of Medicinal Chemistry.37 (5):565–71.doi:10.1021/jm00031a004.PMID8126695.
^Williams PD, Clineschmidt BV, Erb JM, Freidinger RM, Guidotti MT, Lis EV, et al. (November 1995). "1-(1-[4-[(N-acetyl-4-piperidinyl)oxy]-2-methoxybenzoyl]piperidin-4- yl)-4H-3,1-benzoxazin-2(1H)-one (L-371,257): a new, orally bioavailable, non-peptide oxytocin antagonist".Journal of Medicinal Chemistry.38 (23):4634–6.doi:10.1021/jm00023a002.PMID7473590.
^Wyatt PG, Allen MJ, Chilcott J, Foster A, Livermore DG, Mordaunt JE, et al. (May 2002). "Identification of potent and selective oxytocin antagonists. Part 1: indole and benzofuran derivatives".Bioorganic & Medicinal Chemistry Letters.12 (10):1399–404.doi:10.1016/S0960-894X(02)00159-2.PMID11992786.
^Ring RH, Malberg JE, Potestio L, Ping J, Boikess S, Luo B, et al. (April 2006). "Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications".Psychopharmacology.185 (2):218–25.doi:10.1007/s00213-005-0293-z.PMID16418825.S2CID13647805.
