Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is a persuasive evidence that autism is highly heritable and likely to be substantially determined by polygenic mechanisms. Nevertheless, some intriguing findings in children raised in conditions of extreme social deprivation suggest that an autistic-like syndrome may occur as a consequence of environmental conditions. A particularly close model of this human syndrome has been studied in rhesus monkeys for almost half a century. Monkeys reared in pathogenic rearing conditions manifest considerable deficits in social interaction and increased self-directed behaviors. We have been interested in the possibility that disruptions in normal social development in non-human primates might be expressed in neuropeptide systems which have emerged in rodent studies as important candidates for a unique social biology. In recent studies, we have described persistently reduced CSF OT levels in male rhesus monkeys with significant social deficits. We also found that OT levels were positively related to the expression of affiliative social behaviors. Alterations were also detected in both CRH and AVP receptor binding patterns in limbic structures likely to influence social and emotional development. Taken together, these data suggest that abnormal rearing influences the development of brain systems critical to normal social and emotional competence in rhesus monkeys and may contribute to the development of autistic-like symptomatology associated with pathogenic rearing histories.
 ...
PMID:Neuropeptides and non-human primate social deficits associated with pathogenic rearing experience. 1574 49

Vasopressin (also known as arginine vasopressin [AVP]) is a small cyclic peptide that acts at the V1a, V1b and V2 GPCRs to regulate a wide range of physiological functions, including vasoconstriction, smooth muscle contractility, response to stress, and excretion of water and sodium via the kidney. The potential therapeutic applications of AVP receptor ligands have prompted significant interest in this target within the pharmaceutical research community, and several small-molecule drugs targeting the AVP receptor have reached the market, mainly for cardiovascular indications. The development of AVP receptor modulators for the treatment of CNS indications has proven more challenging, and is the focus of this review. The regulatory role of AVP on the hypothalamic-pituitary-adrenal (HPA) axis suggests potential uses for AVP receptor modulators in various CNS indications, including depression, anxiety and post-traumatic stress disorder. Several clinical trials of V1a and V1b receptor antagonists in CNS indications have been conducted, but none of these drugs have reached the market. In recent years, the discovery of the key role of AVP in modulating complex social behaviors has provided a unique opportunity to understand the physiological mechanisms of social interactions. Ultimately, the ongoing research in this field may enable the development of treatments to alleviate the social deficits associated with conditions such as autism and schizophrenia. Given the large unmet medical need in these areas, a renewed interest in the field of CNS-penetrant AVP receptors modulators is expected.
 ...
PMID:Modulation of the vasopressin system for the treatment of CNS diseases. 2081 45

Sex differences in behavior are widespread and often caused by hormonal differences between the sexes. In addition to hormones, the composition and numbers of the sex chromosomes also affect a variety of sex differences. In humans, X-chromosome genes are implicated in neurobehavioral disorders (i.e. fragile-X, autism). To investigate the role of X-chromosome genes in social behavior, we used a mouse model that has atypical sex chromosome configurations resembling Turner (45, XO) and Klinefelter syndromes (47, XXY). We examined a number of behaviors in juvenile mice. Mice with only one copy of most X-chromosome genes, regardless of gonadal sex, were less social in dyadic interaction and social preference tasks. In the elevated plus maze, mice with one X-chromosome spent less time in the distal ends of the open arms as compared to mice with two copies of X-chromosome genes. Using qRTPCR, we noted that amygdala from female mice with one X-chromosome had higher expression levels of vasopressin (Avp) as compared to mice in the other groups. Finally, in plasma from girls with Turner syndrome we detected reduced vasopressin (AVP) concentrations as compared to control patients. These novel findings link sex chromosome genes with social behavior via concentrations of AVP in brain, adding to our understanding of sex differences in neurobehavioral disorders.
...
PMID:Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice. 2546

Vasopressin (AVP) and its receptors play a pivotal role in maintaining body homeostasis under physiological and pathophysiological conditions. As a consequence, the vasopressin system has emerged as an important target for both diagnostic and therapeutic applications in a number of medical conditions. Stoichiometric generation of AVP with copeptin, which is relatively accessible in the blood for measurements, makes copeptin a valuable surrogate of AVP. In this review, we present the regulation of release of AVP and activation of V1a, V1b, and V2 vasopressin receptors under physiological and pathological conditions. We make a survey of the role of AVP in: the regulation of the cardiovascular system; body fluid osmolality; natraemia; endocrine regulation; food intake; metabolism; circadian rhythmicity, immunological processes; and in the formation of learning, memory, cognition, and emotional and social behaviours. We also discuss the significance of the inappropriate functioning of the vasopressin system for: the development of cardiovascular diseases; disturbances of the water-electrolyte balance; energy metabolism; inflammatory processes; pain; neurogenic stress; memory disorders; depression; anxiety; autism; and schizophrenia. The structure and biological properties of peptide and non-peptide agonists and antagonists of V1a, V1b and V2 vasopressin receptors are presented and the potential use of copeptin and the current and likely indications for AVP agonists and antagonists in the diagnosis and therapeutics of multiple pathological conditions is discussed.
 ...
PMID:Vasopressin and Related Peptides; Potential Value in Diagnosis, Prognosis and Treatment of Clinical Disorders. 2811

Oxytocin (OXT) and arginine-vasopressin (AVP) play a key regulatory part in social and affiliative behaviors; two aspects highly compromised in Autism Spectrum Disorder (ASD). Furthermore, variants in the adjacent oxytocin-vasopressin gene regions have been found to be associated with ASD diagnosis and endophenotypes. This review focuses mainly on common OXTr single nucleotide polymorphisms (SNPs), AVPR1a microsatellites and AVPR1b polymorphisms in relation to the development of autism. Although these genes did not surface in genome-wide association studies, evidence supports the hypothesis that these receptors and their polymorphisms are widely involved in the regulation of social behavior, and in modulating neural and physiological pathways contributing to the etiology of ASD. With a specific focus on variants considered to be among the most prevalent in the development of ASD, these issues will be discussed in-depth and suggestions to approach inconsistencies in the present literature will be provided. Translational implications and future directions are deliberated from a short-term and a forward-looking perspective. While the scientific community has made significant progress in enhancing our understanding of ASD, more research is required for the ontology of this disorder to be fully elucidated. By supplementing information related to genetics, highlighting the differences across male and female sexes, this review provides a wider view of the current state of knowledge of OXTr and AVPr mechanisms of functioning, eventually addressing future research in the identification of further risk factors, to build new strategies for early interventions.
 ...
PMID:A Review of Oxytocin and Arginine-Vasopressin Receptors and Their Modulation of Autism Spectrum Disorder. 2948 1

Oxytocin (OT) continues to inspire much research due to its diverse physiological effects. While the best-understood actions of OT are uterine contraction and milk ejection, OT is also implicated in maternal and bonding behaviors, and potentially in CNS disorders such as autism, schizophrenia, and pain. The dissection of the mechanism of action of OT is complicated by the fact that this peptide activates not only its cognate receptor but also vasopressin type 1a (V1a) receptors. In this study, we evaluated OT and a selective OT receptor (OTR) agonist, FE 204409, in an automated assay that measures rat locomotor activity. The results showed: 1) Subcutaneous (sc) administration of OT decreased locomotor behavior (distance traveled, stereotypy, and rearing). This effect was reversed by a V1a receptor (V1aR) antagonist ([Pmp1,Tyr(ME)2]AVP, sc), suggesting that OT acts through peripheral V1aR to inhibit locomotor activity. 2) A selective OTR agonist (FE 204409, sc) increased stereotypy. This effect was reversed by an OTR antagonist dosed icv, suggesting a central OTR site of action. Our findings identify distinct behavioral effects for OT and the selective agonist FE 204409, adding to the growing body of evidence that the V1aR mediates many effects attributed to OT and that peptides administered systemically at supra-physiological doses may activate receptors in the brain. Our studies further emphasize the importance of utilizing selective agonists and antagonists to assess therapeutic indications.
 ...
PMID:Selective and non-selective OT receptor agonists induce different locomotor behaviors in male rats via central OT receptors and peripheral V1a receptors. 2980 52

Oxytocin is an important modulator of human affiliative behaviors, including social skills, human pair bonding, and friendship. CD38 will be discussed as an immune marker and then in more detail the mechanisms of CD38 on releasing brain oxytocin. Mention is made of the paralogue of oxytocin, vasopressin, that has often overlapping and complementary functions with oxytocin on social behavior. Curiously, vasopressin does not require CD38 to be released from the brain. This review discusses the social salience hypothesis of oxytocin action, a novel view of how this molecule influences much of human social behaviors often in contradictory ways. The oxytocinergic-vasopressinergic systems are crucial modulators of broad aspects of human personality. Of special interest are studies of these two hormones in trust related behavior observed using behavioral economic games. This review also covers the role of oxytocin in parenting and parental attachment. In conclusion, the effects of oxytocin on human behavior depend on the individual's social context and importantly as well, the individual's cultural milieu, viz. East and West. ACRONYMS: ACC = Anterior Cingulate ADP = Adenosine diphosphate AQ = Autism Quotient cADPR = Cyclic ADP-ribose CNS = Central nervous system DA = Dopamine eQTLC = Expression Quantitative Trait Loci LC-NE = Locus Coeruleus-Norepinephrine MRI = Magnetic Resonance Imaging OFC = Orbitofrontal cortices OXT = Oxytocin RAGE = Receptor for advanced glycation end-products SARM1 = Sterile Alpha and toll/interleukin-1 receptor motif-containing 1 TRPM2= Transient Receptor Potential Cation Channel Subfamily M Member 2 AVP = Vasopressin.
 ...
PMID:A Novel Role of CD38 and Oxytocin as Tandem Molecular Moderators of Human Social Behavior. 3236 Apr 14

Autism spectrum disorder is a neurodevelopmental disease with increasing occurrence. Recent studies focus on the development of novel V1A receptor antagonists which can influence the core symptoms of autism through the AVP pathway. In this study, we describe the synthesis of new heterocyclic ring systems. These are a novel class of brain-penetrating V1A antagonists with improved metabolic stability and in vivo potency. The efficacy of the compounds was strongly influenced by the position of the chlorine atom, suggesting halogen bond formation between the ligands and the V1A receptor.
 ...
PMID:Discovery of New Heterocyclic Ring Systems as Novel and Potent V1A Receptor Antagonists. 3308 11