Localization of oxytocin binding sites in the human brainstem and upper spinal cord: An autoradiographic study
Department of Physiology, University Medical Center, Geneva, Switzerland.Brain Research (Impact Factor: 2.84). 11/1989; 500(1-2):223-30. DOI: 10.1016/0006-8993(89)90317-X
Two different ligands, tritiated oxytocin and a newly synthesized and monoiodinated oxytocin antagonist, were used to reveal sites which bind oxytocin in the brainstem and upper spinal cord of 12 human subjects. Tissue sections were incubated with either ligand at a concentration close to their respective dissociation constants determined in human uterus and rat brain. Specificity of binding was assessed in presence of unlabelled oxytocin in excess. Comparable results were obtained using tritiated or iodinated ligand. Labelling was most intense in the substantia nigra pars compacta, the substantiae gelatinosae of the caudal spinal trigeminal nucleus and of the dorsal horn of the upper spinal cord, as well as in the medio-dorsal region of the nucleus of the solitary tract. Binding was also detected in the rest of the nucleus of the solitary tract and in other areas, including the oral and interpolar parts of the spinal trigeminal nucleus, the hypoglossal nucleus and the area postrema. Presence of oxytocin binding sites in regions concerned with sensory, autonomic and motor processing suggests that oxytocin could act as a neurotransmitter or neuromodulator in the human central nervous system.
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- "The functional modulation of OT on the enhanced activation of satiety-related responses in the NTS after ADX was reinforced by the increased density of OT-ir fibers in close apposition to NTS neurons activated by food intake following ADX . In support to these data, the identification of OT binding sites and OT-receptors in the NTS has been reported  , indicating that OT projections to the NTS are crucial to the enhanced activation of NTS neurons in meal-induced satiety responses after ADX. "
ABSTRACT: Adrenalectomy (ADX)-induced hypophagia is associated with increased activation of corticotrophin-releasing factor (CRF) and oxytocin (OT) neurons in the paraventricular nucleus of the hypothalamus (PVN) after refeeding. CRF2- and OT-receptor antagonists abolish the hypophagia and the augmented activation of the nucleus of the solitary tract neurons induced by feeding after ADX. In addition, OT-receptor antagonist reversed CRF-induced anorexia. We evaluated the effect of intracerebroventricular pretreatment with CRF2-receptor antagonist, antisauvagine-30 (AS30), on the activation of OT neurons of the PVN in response to refeeding of sham, adrenalectomized (ADX) and ADX rats replaced with corticosterone (ADX+B). In vehicle-pretreated animals, refeeding increased the number of Fos+OT double labeled neurons in the posterior parvocellular subdivision of the PVN (PaPo) of sham, ADX and ADX+B animals, with higher Fos expression and OT neuronal activation in the ADX group. AS30 reversed refeeding-induced increased activation of OT and non-OT neurons in the PaPo in the ADX group. In the medial parvocellular subdivision of the PVN (PaMP) of vehicle-pretreated animals, the number of Fos- and Fos+OT-immunoreactive neurons was increased after refeeding in ADX group. AS30 in the ADX group attenuated the enhanced Fos expression but not the number of Fos+OT double labeled neurons in the PaMP. In conclusion, CRF2-receptor antagonist reverses the increased activation of OT neurons in the PaPo induced by feeding in ADX animals, suggesting that OT neurons might be downstream mediators of CRF effects on satiety-related responses after ADX. Copyright © 2015. Published by Elsevier Ireland Ltd.
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- "Consequently each radioligand binds to both OXTR and AVPR1a, making it difficult to discriminate with confidence the distribution of the two receptors . This lack of selectivity of the radioligands for the primate receptors brings into question the specificity of the receptor binding results in earlier OXTR and AVPR1a mapping studies in human (Loup et al., 1989, 1991) and rhesus macaque (Macaca mulatta) brain tissue (Toloczko et al., 1997). These issues also highlight the importance of overcoming the promiscuous binding profile of the radioligands in primate tissue by using a competitive binding design. "
ABSTRACT: The coppery titi monkey (Callicebus cupreus) is a socially monogamous New World primate that has been studied in the field and the laboratory to investigate the behavioral neuroendocrinology of primate pair bonding and parental care. Arginine vasopressin has been shown to influence male titi monkey pair-bonding behavior, and studies are currently underway to examine the effects of oxytocin on titi monkey behavior and physiology. Here, we use receptor autoradiography to identify the distribution of arginine vasopressin 1a receptor (AVPR1a) and oxytocin receptors (OXTR) in hemispheres of titi monkey brain (n = 5). AVPR1a are diffuse and widespread throughout the brain, but the OXTR distribution is much more limited, with the densest binding being in the hippocampal formation (dentate gyrus, CA1 field) and the presubiculum (layers I and III). Moderate OXTR binding was detected in the nucleus basalis of Meynert, pulvinar, superior colliculus, layer 4C of primary visual cortex, periaqueductal gray (PAG), pontine gray, nucleus prepositus, and spinal trigeminal nucleus. OXTR mRNA overlapped with OXTR radioligand binding, confirming that the radioligand was detecting OXTR protein. AVPR1a binding is present throughout the cortex, especially in cingulate, insular, and occipital cortices, as well as in the caudate, putamen, nucleus accumbens, central amygdala, endopiriform nucleus, hippocampus (CA4 field), globus pallidus, lateral geniculate nucleus, infundibulum, habenula, PAG, substantia nigra, olivary nucleus, hypoglossal nucleus, and cerebellum. Furthermore, we show that, in the titi monkey brain, the OXTR antagonist ALS-II-69 is highly selective for OXTR and that the AVPR1a antagonist SR49059 is highly selective for AVPR1a. Based on these results and the fact that both ALS-II-69 and SR49059 are non-peptide, small-molecule antagonists that should be capable of crossing the blood–brain barrier, these two compounds emerge as excellent candidates for the pharmacological manipulation of OXTR and AVPR1a in future behavioral experiments in titi monkeys and other primate species.
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- "Furthermore, OXTR was detected in NP, a brainstem nucleus that is part of the horizontal gaze holding system and is considered an important neural integrator for the oculomotor system (McCrea and Horn, 2006). The NP also has OXTR binding in the human brain (Loup et al., 1989) and seems to have low levels of OXTR binding in the marmoset brain, which was overlooked in the report (Schorscher-Petcu et al., 2009). OT and AVP acting in these areas may be important regulators of social visual attention, gaze shifting, and gaze stabilization. "
ABSTRACT: Background: Oxytocin (OT) and vasopressin (AVP) are structurally related neuropeptides that act in the brain to modulate the expression of species-specific social behaviors. Research in this field has plowed ahead to investigate the effects of OT in humans, including individuals with autism spectrum disorder (ASD), despite a lack of understanding of the fundamental neurophysiology of these systems in humans and nonhuman primates (NHP) alike. Studying the brains of NHP provides an opportunity to elucidate the neural mechanisms by which OT and AVP modulate social cognition. The coppery titi monkey is a socially monogamous New World primate that has been used to investigate the behavioral neuroendocrinology of social attachment. By establishing the neurochemical basis of pair bonding in this monogamous species, we can better understand how the brain coordinates complex social behaviors more broadly, such as selective attachment, cooperation, and social memory. This research provides valuable insight into the mechanisms underlying social behavior in humans, which can then lead to the development of better treatments for individuals diagnosed with ASD. Objectives: To identify the distribution of the oxytocin receptor (OXTR) and vasopressin 1a receptor (AVPR1a) in order to provide a neuroanatomical foundation for the study of these neuropeptides in mediating social behavior in primates. Methods: We used a pharmacologically optimized, competitive-binding receptor autoradiography protocol to identify the distribution of OXTR and AVPR1a in hemispheres of titi monkey brain (n=5). In this procedure, either the AVPR1a radioligand (125I-LVA) or the OXTR radioligand (125I-OVTA) was incubated on tissue in one of three conditions: 50 pM radioligand alone, or in the presence of either 10 nM of a selective human AVPR1a ligand (SR49059) or 20 nM of a selective human OTR ligand (ALS-II-69). Results: The AVPR1a distribution is widespread throughout the brain, but the OTR distribution is much more limited, with the most abundant binding in the hippocampus, dentate gyrus, presubiculum, nucleus basalis of Meynert, and several hindbrain regions. AVPR1a binding exists throughout the cortex (especially cingulate and occipital cortex), as well as in the caudate, putamen, hippocampus, globus pallidus, lateral geniculate nucleus, periaqueductal grey, substantia nigra, olivary nucleus, and cerebellum. Furthermore, we show that ALS-II-69 reduces OXTR radioligand binding by 40-50% without affecting AVPR1a binding, and that SR49049 is capable of reducing AVPR1a radioligand binding by 75% or more, without significantly affecting binding to OXTR. Conclusions: Both receptors are found in brain regions that modulate visual attention and control orienting responses to visual stimuli. This has important implications for 1) the development of therapies to improve social visual attention and 2) our understanding of neural mechanisms underlying social gaze. Furthermore, both ALS-II-69 and SR49049 emerge as candidates for the pharmacological manipulation of OXTR and AVPR1a in future behavioral experiments in titi monkeys and other primates. These results can ultimately facilitate the development of pharmacological strategies to target the OT and AVP systems for the improvement of social function in individuals with ASD. Funding: MH090776 and MH64692 to LJY; HD053555 and the Good Nature Institute to KLB; P51OD011107 to CNPRC and P51OD11132 to YNPRC.
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