Carbon-11 N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors.
01 Feb 2013-Bioorganic & Medicinal Chemistry Letters (NIH Public Access)-Vol. 23, Iss: 3, pp 902-906
TL;DR: Compound L-368,899 was successfully alkylated with [(11)C]iodomethane to generate the oxytocin receptor selective (2R)-2-amino-N-((2S)-7,7-dimethyl-1-(((4-(o-tolyl)piperazin- 1-yl)sulfonyl)methyl) methyl)bicyclo) with very high radiochemical purity and high specific activity.
About: This article is published in Bioorganic & Medicinal Chemistry Letters.The article was published on 2013-02-01 and is currently open access. It has received 21 citations till now. The article focuses on the topics: L-368,899 & Oxytocin receptor.
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TL;DR: Oxytocin has a wide range of effects over neural activity in response to social and emotional processing, which is further modulated by sex and task specificity, and the magnitude of this neural activation is largest in the temporal lobes.
Abstract: Background: Oxytocin (OXT) plays a prominent role in social cognition and may have clinical applications for disorders such as autism, schizophrenia and social anxiety. The neural basis of its mechanism of action remains unclear. Methods: We conducted a systematic literature review of placebo-controlled imaging studies using OXT as a pharmacological manipulator of brain activity. Results: We identified a total of 21 studies for inclusion in our review, and after applying additional selection criteria, 11 of them were included in our fMRI voxel-based meta-analysis. The results demonstrate consistent alterations in activation of brain regions, including the temporal lobes and insula, during the processing of social stimuli, with some variation dependent on sex and task. The meta-analysis revealed significant left insular hyperactivation after OXT administration, suggesting a potential modulation of neural circuits underlying emotional processing. Limitations: This quantitative review included only a limited number of studies, thus the conclusions of our analysis should be interpreted cautiously. This limited sample size precluded a more detailed exploration of potential confounding factors, such as sex or other demographic factors, that may have affected our meta-analysis. Conclusion: Oxytocin has a wide range of effects over neural activity in response to social and emotional processing, which is further modulated by sex and task specificity. The magnitude of this neural activation is largest in the temporal lobes, and a meta- analysis across all tasks and both sexes showed that the left insula demonstrated the most robust activation to OXT administration.
161 citations
TL;DR: A model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing, however, more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders.
Abstract: Oxytocin and vasopressin are pituitary neuropeptides that have been shown to affect social processes in mammals. There is growing interest in these molecules and their receptors as potential precipitants of, and/or treatments for, social deficits in neurodevelopmental disorders, including autism spectrum disorder. Numerous behavioral-genetic studies suggest that there is an association between these peptides and individual social abilities; however, an explanatory model that links hormonal activity at the receptor level to complex human behavior remains elusive. The following review summarizes the known associations between the oxytocin and vasopressin neuropeptide systems and social neurocircuits in the brain. Following a micro- to macro- level trajectory, current literature on the synthesis and secretion of these peptides, and the structure, function and distribution of their respective receptors is first surveyed. Next, current models regarding the mechanism of action of these peptides on microcircuitry and other neurotransmitter systems are discussed. Functional neuroimaging evidence on the acute effects of exogenous administration of these peptides on brain activity is then reviewed. Overall, a model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing. However, these findings are derived from animal models; more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders.
141 citations
TL;DR: Comparative findings in receptor distributions in rodents and primates are discussed, with perspectives on the functionality of conserved regions of expression in these distinct mammalian clades.
Abstract: In the last several decades, sophisticated experimental techniques have been used to determine the neurobiology of the oxytocin and vasopressin systems in rodents. Using a suite of methodologies, including electrophysiology, site-specific selective pharmacology, receptor autoradiography, in vivo microdialysis, and genetic and optogenetic manipulations, we have gained unprecedented knowledge about how these neuropeptides engage neural circuits to regulate behaviour, particularly social behaviour. Based on this foundation of information from rodent studies, we have started generating new hypotheses and frameworks about how the oxytocin and vasopressin systems could be acting in humans to influence social cognition. However, despite the recent inundation of publications using intranasal oxytocin in humans, we still know very little about the neurophysiology of the oxytocin system in primates more broadly. Furthermore, the design and analysis of these human studies have remained largely uninformed of the potential neurobiological mechanisms underlying their findings. Although the methods available for studying the oxytocin and vasopressin systems in humans are incredibly limited as a result of practical and ethical considerations, there is great potential to fill the gaps in our knowledge by developing better nonhuman primate models of social functioning. Behavioural pharmacology and receptor autoradiography have been used to study the oxytocin and vasopressin systems in nonhuman primates, and there is now great potential to broaden our understanding of the neurobiology of these systems. In this review, we discuss comparative findings in receptor distributions in rodents and primates, with perspectives on the functionality of conserved regions of expression in these distinct mammalian clades. We also identify specific ways that established technologies can be used to answer basic research questions in primates. Finally, we highlight areas of future research in nonhuman primates that are experimentally poised to yield critical insights into the anatomy, physiology and behavioural effects of the oxytocin system, given its remarkable translational potential.
138 citations
TL;DR: The current state of the art in intranasal psychopharmacological agent delivery research and current challenges using this administration route are described, and important aspects of nose-to-brain delivery that may improve the efficacy of these new therapies in future research are discussed.
Abstract: Accumulating research demonstrates the potential of intranasal delivery of psychopharmacological agents to treat a range of psychiatric disorders and symptoms. It is believed that intranasal administration offers both direct and indirect pathways to deliver psychopharmacological agents to the central nervous system. This administration route provides a unique opportunity to repurpose both old drugs for new uses and improve currently approved drugs that are indicated for other administration routes. Despite this promise, however, the physiology of intranasal delivery and related assumptions behind the bypassing of the blood brain barrier is seldom considered in detail in clinical trials and translational research. In this review, we describe the current state of the art in intranasal psychopharmacological agent delivery research and current challenges using this administration route, and discuss important aspects of nose-to-brain delivery that may improve the efficacy of these new therapies in future research. We also highlight current gaps in the literature and suggest how research can directly examine the assumptions of nose-to-brain delivery of psychopharmacological agents in humans.
81 citations
TL;DR: Understanding the effective sites of action for OXT via its receptor will help refine hypotheses about the roles of this important neuropeptide in the experience‐dependent development and expression of species‐typical social behavior.
Abstract: Oxytocin (OXT) signaling through the OXT receptor plays a significant role in a variety of physiological processes throughout the lifespan. OXT's effects depend on the tissue distribution of the receptor. This tissue specificity is dynamic and changes across development, and also varies with sex, experience, and species. The purpose of this review is to highlight these themes with examples from several life stages and several species. Important knowledge gaps will also be emphasized. Understanding the effective sites of action for OXT via its receptor will help refine hypotheses about the roles of this important neuropeptide in the experience-dependent development and expression of species-typical social behavior. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 143-157, 2017.
61 citations
References
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TL;DR: There is growing evidence that the neuropeptides oxytocin and vasopressin modulate complex social behavior and social cognition and suggest that variation in the genes encoding their receptors may contribute to variation in human social behavior by altering brain function.
Abstract: There is growing evidence that the neuropeptides oxytocin and vasopressin modulate complex social behavior and social cognition. These ancient neuropeptides display a marked conservation in gene structure and expression, yet diversity in the genetic regulation of their receptors seems to underlie natural variation in social behavior, both between and within species. Human studies are beginning to explore the roles of these neuropeptides in social cognition and behavior and suggest that variation in the genes encoding their receptors may contribute to variation in human social behavior by altering brain function. Understanding the neurobiology and neurogenetics of social cognition and behavior has important implications, both clinically and for society.
1,445 citations
TL;DR: It is demonstrated that OT acts in the medial amygdala during the initial exposure to facilitate social recognition in the mouse, and OT given before, but not after, the initial encounter restores social Recognition in OT knock-out mice.
Abstract: Oxytocin (OT) knock-out mice fail to recognize familiar conspecifics after repeated social exposures, despite normal olfactory and spatial learning abilities. OT treatment fully restores social recognition. Here we demonstrate that OT acts in the medial amygdala during the initial exposure to facilitate social recognition. OT given before, but not after, the initial encounter restores social recognition in OT knock-out mice. Using c-Fos immunoreactivity (Fos-IR) as a marker of neuronal activation in this initial encounter, we found similar neuronal activation in the wild-type (WT) and OT knock-out mouse in olfactory bulbs, piriform cortex, cortical amygdala, and the lateral septum. Wild-type, but not OT knock-out mice exhibited an induction of Fos-IR in the medial amygdala. Projections sites of the medial amygdala also failed to show a Fos-IR induction in the OT knock-out mice. OT knock-out, but not WT, mice showed dramatic increases in Fos-IR in the somatosensory cortex and the hippocampus, suggesting alternative processing of social cues in these animals. With site-specific injections of OT and an OT antagonist, we demonstrate that OT receptor activation in the medial amygdala is both necessary and sufficient for social recognition in the mouse.
995 citations
TL;DR: The role of oxytocin in the regulation of prosocial interactions is reviewed, the neuroanatomy of the central oxytocIn system is discussed, and the nature of Oxytocin release within the brain is discussed.
719 citations
TL;DR: The data suggest that OT abnormalities may exist in autism, and that more direct investigation of central nervous system OT function is warranted, after making inferences to central OT functioning from peripheral measurement.
686 citations
TL;DR: Data suggest an involvement of OXTR in the susceptibility to autism, and replication is important.
527 citations