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: 2.83). 11/1989; 500(1-2):223-30. DOI: 10.1016/0006-8993(89)90317-X
Source: PubMed

ABSTRACT 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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    • "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. "
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    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.
    Neuroscience 07/2014; 273:12–23. DOI:10.1016/j.neuroscience.2014.04.055 · 3.33 Impact Factor
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    • "Neuroscience 253 (2013) 155–164 amygdala or the hippocampus. However, the validity of the Loup et al. (1989, 1991) studies has been brought into question by evidence that 125 I-OTA binds V1a as potently as OTRs in the rhesus monkey brain (Toloczko et al., 1997). "
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    ABSTRACT: The neuropeptide oxytocin (OT) regulates rodent, primate and human social behaviors and stress responses. OT binding studies employing (125)I-d(CH2)5-[Tyr(Me)2,Thr4,Tyr-NH2(9)] ornithine vasotocin ((125)I-OTA), has been used to locate and quantify OTRs in numerous areas of the rat brain. This ligand has also been applied to locating OTRs in human brain. The results of the latter studies, however, have been brought into question because of subsequent evidence that (125)I-OTA is much less selective for OTR vs. vasopressin receptors in primate brain. Previously we used a monoclonal antibody directed toward a region of the human OTR to demonstrate selective immunostaining of cell bodies and fibers in the preoptic-anterior hypothalamic area and ventral septum of a cynomolgus monkey (Boccia et al., 2001). The present study employed the same monoclonal antibody to study the location of OTRs in tissue blocks containing cortical, limbic and brainstem areas dissected from fixed adult, human female brains. OTRs were visualized in discrete cell bodies and/or fibers in the central and basolateral regions of the amygdala, medial preoptic area, anterior and ventromedial hypothalamus, olfactory nucleus, vertical limb of the diagonal band, ventrolateral septum, anterior cingulate and hypoglossal and solitary nuclei. OTR staining was not observed in the hippocampus (including CA2 and CA3), parietal cortex, raphe nucleus, nucleus ambiguus or pons. These results suggest that there are some similarities, but also important differences, in the locations of OTRs in human and rodent brains. Immunohistochemistry utilizing a monoclonal antibody provides specific localization of OTRs in human brain and thereby provides opportunity to further study OTR in human development and psychiatric conditions.
    Neuroscience 09/2013; 253. DOI:10.1016/j.neuroscience.2013.08.048 · 3.33 Impact Factor
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    • "Research has demonstrated that activation of the brainstem is significantly attenuated following oxytocin administration (Baumgartner et al., 2008), likely through the mediation of activity via these amygdalar projections (Huber et al., 2005). Complementing this indirect influence of oxytocin on brainstem activity, functional oxytocin receptors have been identified within the human central gray, among other brainstem regions (Loup et al., 1989), suggesting that the neuropeptide directly affects brainstem structure and function. Indeed, direct administration of oxytocin into the periaqueductal gray has been shown to attenuate anxiety-related behaviors in postpartum rats (Figueira et al., 2008). "
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    ABSTRACT: The oxytocin system plays a significant role in modulating stress responses in animals and humans; perturbations in this system may contribute to the pathogenesis of psychiatric disorder. Attempts to identify clinically relevant genetic variants in the oxytocin system have yielded associations between polymorphisms of the oxytocin receptor (OXTR) gene and both autism and major depression. To date, however, little is known about how such variants affect brain structures implicated in these disorders. Applying a manual tracing procedure to high-resolution structural magnetic resonance images, amygdala volumes were measured in 51 girls genotyped on OXTR rs2254298(G>A), a single nucleotide polymorphism associated with psychopathology. Results of this study indicate that despite having greater gray matter volume, participants homozygous for the G allele were characterized by smaller volumes of both left and right amygdala than were carriers of the A allele. A subsequent whole-brain voxel-based morphometry analysis revealed additional genotype-mediated volumetric group differences in the posterior brain stem and dorsomedial anterior cingulate cortex. These findings highlight one neurobiological pathway by which oxytocin gene variants may increase risk for psychopathology. Further research is needed to characterize the mechanism by which this polymorphism contributes to anatomical variability and to identify functional correlates of these alterations in regional brain volume.
    Psychoneuroendocrinology 07/2011; 36(6):891-7. DOI:10.1016/j.psyneuen.2010.12.004 · 5.59 Impact Factor
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