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Sample records for brain receptors mitogenesis

  1. Endothelium in brain: Receptors, mitogenesis, and biosynthesis in glial cells

    International Nuclear Information System (INIS)

    MacCumber, M.W.; Ross, C.A.; Snyder, S.H.

    1990-01-01

    The authors have explored the cellular loci of endothelin (ET) actions and formation in the brain, using cerebellar mutant mice was well as primary and continuous cell cultures. A glial role is favored by several observations: (1) mutant mice lacking neuronal Purkinje cells display normal ET receptor binding and enhanced stimulation by ET of inositolphospholipid turnover; (ii) in weaver mice lacking neuronal granule cells, ET stimulation of inositolphospholipid turnover is not significantly diminished; (iii) C 6 glioma cells and primary cultures of cerebellar astroglia exhibit substantial ET receptor binding and ET-induced stimulation of inositolphospholipid turnover; (iv) ET promotes mitogenesis of C 6 glioma cells and primary cerebellar astroglia; and (v) primary cultures of cerebellar astroglia contain ET mRNA. ET also appears to have a neuronal role, since it stimulates inositolphospholipid turnover in primary cultures of cerebellar granule cells, and ET binding declines in granule cell-deficient mice. Thus, ET can be produced by glia and act upon both glia and neurons in a paracrine fashion

  2. Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis.

    Science.gov (United States)

    Mohammadi, M; Dionne, C A; Li, W; Li, N; Spivak, T; Honegger, A M; Jaye, M; Schlessinger, J

    1992-08-20

    Stimulation of growth factor receptors with tyrosine kinase activity is followed by rapid receptor dimerization, tyrosine autophosphorylation and phosphorylation of signalling molecules such as phospholipase C gamma (PLC gamma) and the ras GTPase-activating protein. PLC gamma and GTPase-activating protein bind to specific tyrosine-phosphorylated regions in growth factor receptors through their src-homologous SH2 domains. Growth factor-induced tyrosine phosphorylation of PLC gamma is essential for stimulation of phosphatidylinositol hydrolysis in vitro and in vivo. We have shown that a short phosphorylated peptide containing tyrosine at position 766 from a conserved region of the fibroblast growth factor (FGF) receptor is a binding site for the SH2 domain of PLC gamma (ref. 8). Here we show that an FGF receptor point mutant in which Tyr 766 is replaced by a phenylalanine residue (Y766F) is unable to associate with and tyrosine-phosphorylate PLC gamma or to stimulate hydrolysis of phosphatidylinositol. Nevertheless, the Y766F FGF receptor mutant can be autophosphorylated, and can phosphorylate several cellular proteins and stimulate DNA synthesis. Our data show that phosphorylation of the conserved Tyr 766 of the FGF receptor is essential for phosphorylation of PLC gamma and for hydrolysis of phosphatidylinositol, but that elimination of this hydrolysis does not affect FGF-induced mitogenesis.

  3. The NK-1 Receptor Antagonist L-732,138 Induces Apoptosis and Counteracts Substance P-Related Mitogenesis in Human Melanoma Cell Lines

    Directory of Open Access Journals (Sweden)

    Miguel Muñoz

    2010-04-01

    Full Text Available It has been recently demonstrated that substance P (SP and neurokinin-1 (NK-1 receptor antagonists induce cell proliferation and cell inhibition in human melanoma cells, respectively. However, the antitumor action of the NK-1 receptor antagonist L-732,138 on such cells is unknown. The aim of this study was to demonstrate an antitumor action of L-732,138 against three human melanoma cell lines (COLO 858, MEL HO, COLO 679. We found that L-732,138 elicits cell growth inhibition in a concentration dependent manner in the melanoma cells studied. Moreover, L-732,138 blocks SP mitogen stimulation. The specific antitumor action of L-732,138 occurred through the NK-1 receptor and melanoma cell death was by apoptosis. These findings indicate that the NK-1 receptor antagonist L-732,138 could be a new antitumor agent in the treatment of human melanoma.

  4. The NK-1 Receptor Antagonist L-732,138 Induces Apoptosis and Counteracts Substance P-Related Mitogenesis in Human Melanoma Cell Lines

    Energy Technology Data Exchange (ETDEWEB)

    Muñoz, Miguel, E-mail: mmunoz@cica.es; Rosso, Marisa; González-Ortega, Ana [Research Laboratory on Neuropeptides, Virgen del Rocío University Hospital, Sevilla (Spain); Coveñas, Rafael [Institute of Neurosciences of Castilla y León (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems (Laboratory 14), Salamanca (Spain)

    2010-04-20

    It has been recently demonstrated that substance P (SP) and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition in human melanoma cells, respectively. However, the antitumor action of the NK-1 receptor antagonist L-732,138 on such cells is unknown. The aim of this study was to demonstrate an antitumor action of L-732,138 against three human melanoma cell lines (COLO 858, MEL HO, COLO 679). We found that L-732,138 elicits cell growth inhibition in a concentration dependent manner in the melanoma cells studied. Moreover, L-732,138 blocks SP mitogen stimulation. The specific antitumor action of L-732,138 occurred through the NK-1 receptor and melanoma cell death was by apoptosis. These findings indicate that the NK-1 receptor antagonist L-732,138 could be a new antitumor agent in the treatment of human melanoma.

  5. Prolactin-stimulated mitogenesis in the Nb2 rat lymphoma cell: Lack of protoporphyrin IX effects

    Energy Technology Data Exchange (ETDEWEB)

    Gerrish, K.E.; Putnam, C.W.; Laird, H.E. II (Univ. of Arizona, Tucson (USA))

    1990-01-01

    Pharmacological characterization of the Nb2 cell peripheral-type benzodiazepine receptor (PBR) was determined using selected 1,4-benzodiazepines, PK 11195, and protoporphyrin IX (PPIX) to compete for specific ({sup 3}H) Ro5-4864 binding. These data suggest that PPIX possesses an affinity for the Nb2 cell PBR. We have previously reported that the peripheral benzodiazepine ligands, Ro5-4864 and PK 11195, modulate prolactin-stimulated mitogenesis in the Nb2 cell. In contrast, PPIX, a putative endogenous ligand for the PBR had no effect on prolactin-stimulated mitogenesis in the Nb2 cell over the concentration range from 10{sup {minus}15} M to 10{sup {minus}6} M. Taken together these data show that PPIX has an affinity for the Nb2 cell PBR but does not modulate prolactin-stimulated mitogenesis at concentrations which should bind to the Nb2 cell PBR.

  6. Stimulation of aortic smooth muscle cell mitogenesis by serotonin

    International Nuclear Information System (INIS)

    Nemecek, G.M.; Coughlin, S.R.; Handley, D.A.; Moskowitz, M.A.

    1986-01-01

    Bovine aortic smooth muscle cells in vitro responded to 1 nM to 10 μM serotonin with increased incorporation of [ 3 H]thymidine into DNA. The mitogenic effect of serotonin was half-maximal at 80 nM and maximal above 1 μM. At a concentration of 1 μM, serotonin stimulated smooth muscle cell mitogenesis to the same extent as human platelet-derived growth factor (PDGF) at 12 ng/ml. Tryptamine was ≅ 1/10th as potent as serotonin as a mitogen for smooth muscle cells. Other indoles that are structurally related to serotonin (D- and L-tryptophan, 5-hydroxy-L-tryptophan, N-acetyl-5-hydroxytryptamine, melatonin, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophol) and quipazine were inactive. The stimulatory effect of serotonin on smooth muscle cell DNA synthesis required prolonged (20-24 hr) exposure to the agonist and was attenuated in the presence of serotonin D receptor antagonists. When smooth muscle cells were incubated with submaximal concentrations of serotonin and PDGF, synergistic rather than additive mitogenic responses were observed. These data indicate that serotonin has a significant mitogenic effect on smooth muscle cells in vitro, which appears to be mediated by specific plasma membrane receptors

  7. Signal transduction in mitogenesis: Further evidence for multiple pathways

    International Nuclear Information System (INIS)

    Rozengurt, E.; Erusalimsky, J.; Mehmet, H.; Morris, C.; Nanberg, E.; Sinnett-Smith, J.

    1988-01-01

    Growth factors are implicated in a wide variety of physiological and pathological processes, including embryogenesis, hematopoiesis, would healing, immune responses, atherosclerosis, and neoplasia. An important link between growth factors and their receptors and oncogene products has also been established. Thus, the elucidation of the mechanism of action of growth factors has emerged as one of the fundamental problems in biology and may prove crucial for understanding the unrestrained proliferation of cancer cells. A new and intriguing development is the discovery that neuropeptides localized in neural and neuroendocrine cells of mammalian tissue can also act as growth factors for cells in culture. Furthermore, indirect evidence is accumulating that the mitogenic effects of neuropeptides may be relevant for a variety of long-term biological processes, including development and oncogenesis. In this context, the peptides of the bombesin family are of particular significance. These peptides are potent mitogens for Swiss 3T3 cells and may act as autocrine growth factors for small cell lung cancer. Here, the authors summarize their recent studies using bombesin-like peptides for elucidating the signal transduction pathways leading to mitogenesis and compare these pathways with those elicited by other growth factors

  8. Peptide YY receptors in the brain

    International Nuclear Information System (INIS)

    Inui, A.; Oya, M.; Okita, M.

    1988-01-01

    Radiolabelled ligand binding studies demonstrated that specific receptors for peptide YY are present in the porcine as well as the canine brains. Peptide YY was bound to brain tissue membranes via high-affinity (dissociation constant, 1.39 X 10(-10)M) and low-affinity (dissociation constant, 3.72 X 10(-8)M) components. The binding sites showed a high specificity for peptide YY and neuropeptide Y, but not for pancreatic polypeptide or structurally unrelated peptides. The specific activity of peptide YY binding was highest in the hippocampus, followed by the pituitary gland, the hypothalamus, and the amygdala of the porcine brain, this pattern being similarly observed in the canine brain. The results suggest that peptide YY and neuropeptide Y may regulate the function of these regions of the brain through interaction with a common receptor site

  9. Enhanced mitogenesis in stromal vascular cells derived from subcutaneous adipose tissue of Wagyu compared with those of Angus cattle.

    Science.gov (United States)

    Wei, S; Fu, X; Liang, X; Zhu, M J; Jiang, Z; Parish, S M; Dodson, M V; Zan, L; Du, M

    2015-03-01

    Japanese Wagyu cattle are well known for their extremely high marbling and lower subcutaneous adipose tissue compared with Angus cattle. However, mechanisms for differences in adipose deposition are unknown. The objective of this paper was to evaluate breed differences in the structure of subcutaneous adipose tissue, adipogenesis, and mitogenesis of stromal vascular (SV) cells between Wagyu and Angus cattle. Subcutaneous biopsy samples were obtained from 5 Wagyu (BW = 302 ± 9 kg) and 5 Angus (BW = 398 ± 12 kg) heifers at 12 mo of age, and samples were divided into 3 pieces for histological examination, biochemical analysis, and harvest of SV cells. Adipogenesis of SV cells was assessed by the expression of adipogenic markers and Oil Red-O staining, while mitogenesis was evaluated by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium dromide) test, phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB; AKT). Based on histological analysis, Wagyu had larger adipocytes compared with Angus. At the tissue level, protein expression of peroxisome proliferator-activated receptor γ (PPARG) in Wagyu was much lower compared with that of Angus. Similarly, a lower mRNA expression of PPARG was found in Wagyu SV cells. No significant difference was observed for the zinc finger protein 423 (ZNF423) expression between Wagyu and Angus. As assessed by Oil Red-O staining, Wagyu SV cells possessed a notable trend of lower adipogenic capability. Interestingly, higher mitogenic ability was discovered in Wagyu SV cells, which was associated with an elevated phosphorylation of ERK1/2. There was no difference in AKT phosphorylation of SV cells between Wagyu and Angus. Moreover, exogenous fibroblast growth factor 2 (FGF2) enhanced mitogenesis and ERK1/2 phosphorylation of SV cells to a greater degree in Angus compared with that in Wagyu. Expression of transforming growth factor β 3 (TGFB3) and bone morphogenetic protein 2 (BMP2) in Wagyu SV

  10. Purification of a putative brain somatostatin receptor

    International Nuclear Information System (INIS)

    He, Haitao; Johnson, K.; Thermos, K.; Reisine, T.

    1989-01-01

    The brain somatostatin receptor was purified by affinity chromatographic techniques. A protein of 60 kDa could be purified from rat brain. The protein was eluted from a [D-Trp 8 ]SRIF affinity column with either sodium acetate (pH 5.5) or free [D-Trp 8 ]SRIF. The binding of the protein to the affinity column was prevented by free [D-Trp 8 ]SRIF or the stable SRIF analogue SMS 201-996 but not by the inactive somatostatin 28-(1-14). The purified receptor could be covalently labeled by the 125 I-labeled SRIF analogue CGP 23996. Excess [D-Trp 8 ]SRIF blocked the binding of 125 I-labeled CGP 23996 to the purified receptor, but somatostatin 28-(1-14) did not affect the binding. A 60-kDa protein was also purified from the anterior pituitary cell line AtT-20, which has a high expression of SRIF receptors. In contrast, no 60-kDa protein could be purified from CHO cells, which have no detectable SRIF receptors. These findings present evidence for the purification of the SRIF receptor

  11. Distribution of melatonin receptor in human fetal brain

    Institute of Scientific and Technical Information of China (English)

    WANG Guo-quan; SHAO Fu-yuan; ZHAO Ying; LIU Zhi-min

    2001-01-01

    Objective: To study the distribution of 2 kinds of melatonin receptor subtypes (mtl and MT2) in human fetal brain. Methods: The fetal brain tissues were sliced and the distribution ofmelatonin receptors in human fetal brain were detected using immunohistochemistry and in situ hybridization. Results: Melatonin receptor mtl existed in the cerebellun and hypothalamus, melatonin receptor MT2 exists in hypothalamus, occipital and medulla. Conclusion: Two kinds of melatonin receptors, mtl and MT2 exist in the membrane and cytosol of brain cells, indicating that human fetal brain is a target organ of melatonin.

  12. Positron emission tomography studies of brain receptors

    International Nuclear Information System (INIS)

    Maziere, B.; Maziere, M.

    1991-01-01

    Probing the regional distribution and affinity of receptors in the brain, in vivo, in human and non human primates has become possible with the use of selective ligands labelled with positron emitting radionuclides and positron emission tomography (PET). After describing the techniques used in positron emission tomography to characterize a ligand receptor binding and discussing the choice of the label and the limitations and complexities of the in vivo approach, the results obtained in the PET studies of various neurotransmission systems: dopaminergic, opiate, benzodiazepine, serotonin and cholinergic systems are reviewed

  13. Basic calcium phosphate crystal-induced Egr-1 expression stimulates mitogenesis in human fibroblasts

    International Nuclear Information System (INIS)

    Zeng, Xiao R.; Sun Yubo; Wenger, Leonor; Cheung, Herman S.

    2005-01-01

    Previously, we have reported that basic calcium phosphate (BCP) crystals stimulate mitogenesis and synthesis of matrix metalloproteinases in cultured human foreskin and synovial fibroblasts. However, the detailed mechanisms involved are still unclear. In the present study, using RT-PCR and Egr-1 promoter analysis we showed that BCP crystals could stimulate early growth response gene Egr-1 transcription through a PKCα-dependent p44/p42 MAPK pathway. Using a retrovirus gene expression system (Clontech) to overexpress Egr-1 in human fibroblast BJ-1 cells resulted in promotion of mitogenesis measured either by MTT cell proliferation analysis or by direct cell counting. The results demonstrate that Egr-1 may play a key role in mediating BCP crystal-induced synovial fibroblast mitogenesis

  14. Development of antibodies against the rat brain somatostatin receptor.

    Science.gov (United States)

    Theveniau, M; Rens-Domiano, S; Law, S F; Rougon, G; Reisine, T

    1992-05-15

    Somatostatin (SRIF) is a neurotransmitter in the brain involved in the regulation of motor activity and cognition. It induces its physiological actions by interacting with receptors. We have developed antibodies against the receptor to investigate its structural properties. Rabbit polyclonal antibodies were generated against the rat brain SRIF receptor. These antibodies (F4) were able to immunoprecipitate solubilized SRIF receptors from rat brain and the cell line AtT-20. The specificity of the interaction of these antibodies with SRIF receptors was further demonstrated by immunoblotting. F4 detected SRIF receptors of 60 kDa from rat brain and adrenal cortex and the cell lines AtT-20, GH3, and NG-108, which express high densities of SRIF receptors. They did not detect immunoreactive material from rat liver or COS-1, HEPG, or CRL cells, which do not express functional SRIF receptors. In rat brain, 60-kDa immunoreactivity was detected by F4 in the hippocampus, cerebral cortex, and striatum, which have high densities of SRIF receptors. However, F4 did not interact with proteins from cerebellum and brain stem, which express few SRIF receptors. Immunoreactive material cannot be detected in rat pancreas or pituitary, which have been reported to express a 90-kDa SRIF receptor subtype. The selective detection of 60-kDa SRIF receptors by F4 indicates that the 60- and 90-kDa SRIF receptor subtypes are immunologically distinct. The availability of antibodies that selectively detect native and denatured brain SRIF receptors provides us with a feasible approach to clone the brain SRIF receptor gene(s).

  15. Distribution of cellular HSV-1 receptor expression in human brain.

    Science.gov (United States)

    Lathe, Richard; Haas, Juergen G

    2017-06-01

    Herpes simplex virus type 1 (HSV-1) is a neurotropic virus linked to a range of acute and chronic neurological disorders affecting distinct regions of the brain. Unusually, HSV-1 entry into cells requires the interaction of viral proteins glycoprotein D (gD) and glycoprotein B (gB) with distinct cellular receptor proteins. Several different gD and gB receptors have been identified, including TNFRSF14/HVEM and PVRL1/nectin 1 as gD receptors and PILRA, MAG, and MYH9 as gB receptors. We investigated the expression of these receptor molecules in different areas of the adult and developing human brain using online transcriptome databases. Whereas all HSV-1 receptors showed distinct expression patterns in different brain areas, the Allan Brain Atlas (ABA) reported increased expression of both gD and gB receptors in the hippocampus. Specifically, for PVRL1, TNFRFS14, and MYH9, the differential z scores for hippocampal expression, a measure of relative levels of increased expression, rose to 2.9, 2.9, and 2.5, respectively, comparable to the z score for the archetypical hippocampus-enriched mineralocorticoid receptor (NR3C2, z = 3.1). These data were confirmed at the Human Brain Transcriptome (HBT) database, but HBT data indicate that MAG expression is also enriched in hippocampus. The HBT database allowed the developmental pattern of expression to be investigated; we report that all HSV1 receptors markedly increase in expression levels between gestation and the postnatal/adult periods. These results suggest that differential receptor expression levels of several HSV-1 gD and gB receptors in the adult hippocampus are likely to underlie the susceptibility of this brain region to HSV-1 infection.

  16. Neuropeptide Y receptors in rat brain: autoradiographic localization

    International Nuclear Information System (INIS)

    Martel, J.C.; St-Pierre, S.; Quirion, R.

    1986-01-01

    Neuropeptide Y (NPY) receptor binding sites have been characterized in rat brain using both membrane preparations and receptor autoradiography. Radiolabelled NPY binds with high affinity and specificity to an apparent single class of sites in rat brain membrane preparations. The ligand selectivity pattern reveals strong similarities between central and peripheral NPY receptors. NPY receptors are discretely distributed in rat brain with high densities found in the olfactory bulb, superficial layers of the cortex, ventral hippocampus, lateral septum, various thalamic nuclei and area postrema. The presence of high densities of NPY and NPY receptors in such areas suggests that NPY could serve important functions as a major neurotransmitter/neuromodulator in the central nervous system

  17. A prototypical Sigma-1 receptor antagonist protects against brain ischemia

    OpenAIRE

    Schetz, John A.; Perez, Evelyn; Liu, Ran; Chen, Shiuhwei; Lee, Ivan; Simpkins, James W.

    2007-01-01

    Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this s...

  18. Risperidone treatment increases CB1 receptor binding in rat brain

    DEFF Research Database (Denmark)

    Secher, Anna; Husum, Henriette; Holst, Birgitte

    2010-01-01

    , the ghrelin receptor, neuropeptide Y, adiponectin and proopiomelanocortin. We investigated whether the expression of these factors was affected in rats chronically treated with the antipsychotic risperidone. METHODS: Male Sprague-Dawley rats were treated with risperidone (1.0 mg/kg/day) or vehicle (20...... showed that risperidone treatment altered CB(1) receptor binding in the rat brain. Risperidone-induced adiposity and metabolic dysfunction in the clinic may be explained by increased CB(1) receptor density in brain regions involved in appetite and regulation of metabolic function....

  19. The meth brain: methamphetamines alter brain functions via NMDA receptors

    Czech Academy of Sciences Publication Activity Database

    Proft, Juliane; Weiss, Norbert

    2015-01-01

    Roč. 34, č. 1 (2015), s. 1-3 ISSN 0231-5882 R&D Projects: GA ČR GA15-13556S Institutional support: RVO:61388963 Keywords : ion channel * methamphetamine * piriform cortex * NMDA receptor * AMPA receptor Subject RIV: CE - Biochemistry Impact factor: 0.892, year: 2015

  20. Distribution of corticotropin-releasing factor receptors in primate brain

    International Nuclear Information System (INIS)

    Millan, M.A.; Jacobowitz, D.M.; Hauger, R.L.; Catt, K.J.; Aguilera, G.

    1986-01-01

    The distribution and properties of receptors for corticotropin-releasing factor (CRF) were analyzed in the brain of cynomolgus monkeys. Binding of [ 125 I]tyrosine-labeled ovine CRF to frontal cortex and amygdala membrane-rich fractions was saturable, specific, and time- and temperature-dependent, reaching equilibrium in 30 min at 23 0 C. Scatchard analysis of the binding data indicated one class of high-affinity sites with a K/sub d/ of 1 nM and a concentration of 125 fmol/mg. As in the rat pituitary and brain, CRF receptors in monkey cerebral cortex and amygdala were coupled to adenylate cyclase. Autoradiographic analysis of specific CRF binding in brain sections revealed that the receptors were widely distributed in the cerebral cortex and limbic system. Receptor density was highest in the pars tuberalis of the pituitary and throughout the cerebral cortex, specifically in the prefrontal, frontal, orbital, cingulate, insular, and temporal areas, and in the cerebellar cortex. A low binding density was present in the superior colliculus, locus coeruleus, substantia gelatinosa, preoptic area, septal area, and bed nucleus of the stria terminalis. These data demonstrate that receptors for CRF are present within the primate brain at areas related to the central control of visceral function and behavior, suggesting that brain CRF may serve as a neurotransmitter in the coordination of endocrine and neural mechanisms involved in the response to stress

  1. The double bromodomain protein Brd2 promotes B cell expansion and mitogenesis.

    Science.gov (United States)

    Belkina, Anna C; Blanton, Wanda P; Nikolajczyk, Barbara S; Denis, Gerald V

    2014-03-01

    Bromodomain-containing transcriptional regulators represent new epigenetic targets in different hematologic malignancies. However, bromodomain-mediated mechanisms that couple histone acetylation to transcription in lymphopoiesis and govern mature lymphocyte mitogenesis are poorly understood. Brd2, a transcriptional coregulator that contains dual bromodomains and an extraterminal domain (the BET family), couples chromatin to cell-cycle progression. We reported previously the first functional characterization of a BET protein as an effector of mammalian mitogenic signal transduction: Eμ-Brd2 Tg mice develop "activated B cell" diffuse large B cell lymphoma. No other animal models exist for genetic or lentiviral expression of BET proteins, hampering testing of novel anti-BET anticancer drugs, such as JQ1. We transduced HSCs with Brd2 lentivirus and reconstituted recipient mice to test the hypothesis that Brd2 regulates hematopoiesis in BM and mitogenesis in the periphery. Forced expression of Brd2 provides an expansion advantage to the donor-derived B cell compartment in BM and increases mature B cell mitogenic responsiveness in vitro. Brd2 binds the cyclin A promoter in B cells, shown by ChIP, and increases cyclin A mRNA and protein levels, and S-phase progression in vitro in mitogen-stimulated primary B cells, but not T cells, reinforcing results from Eμ-Brd2 mice. The small molecule BET inhibitor JQ1 reduces B cell mitogenesis, consistent with the interpretation that BET inhibitors are antiproliferative. Brd2-specific knockdown experiments show that Brd2 is also required for hematopoiesis. We conclude that Brd2 plays a critical, independent role in regulation of mitogenic response genes, particularly cyclin A, in B cells.

  2. Brain nuclear receptors and body weight regulation

    Science.gov (United States)

    Neural pathways, especially those in the hypothalamus, integrate multiple nutritional, hormonal, and neural signals, resulting in the coordinated control of body weight balance and glucose homeostasis. Nuclear receptors (NRs) sense changing levels of nutrients and hormones, and therefore play essent...

  3. GABAA Receptors, Anesthetics and Anticonvulsants in Brain Development

    Science.gov (United States)

    Henschel, Oliver; Gipson, Keith E.; Bordey, Angelique

    2008-01-01

    GABA, acting via GABAA receptors, is well-accepted as the main inhibitory neurotransmitter of the mature brain, where it dampens neuronal excitability. The receptor's properties have been studied extensively, yielding important information about its structure, pharmacology, and regulation that are summarized in this review. Several GABAergic drugs have been commonly used as anesthetics, sedatives, and anticonvulsants for decades. However, findings that GABA has critical functions in brain development, in particular during the late embryonic and neonatal period, raise worthwhile questions regarding the side effects of GABAergic drugs that may lead to long-term cognitive deficits. Here, we will review some of these drugs in parallel with the control of CNS development that GABA exerts via activation of GABAA receptors. This review aims to provide a basic science and clinical perspective on the function of GABA and related pharmaceuticals acting at GABAA receptors. PMID:18537647

  4. Fundamental study on brain receptor mapping by neuronuclear medicine imaging. Quantitation of receptor autoradiography in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Tsuji, Shiro

    1988-04-01

    The usefulness of autoradiography in the quantitation of the rat brain receptor was evaluated. H-3 spiperone, H-3 quinuclidinyl benzylate (QNB), H-3 muscimol, H-3 diprenorphine, H-3 ketanserin, and H-3 dihydroalprenolol hydrochloride were used for autoradiography. Satisfactory autoradiograms with these H-3 labeled ligants were obtained for incubation time, washing time, and binding curve. The video digitizer system was the most suitable in autoradiography. Using appropriate conditions for the ligand-receptor interaction, receptor autoradiography and in vitro receptor assay were concordant as for the the number of maximum binding sites (Bmax) of the muscarinic acetylcholine receptor and equilibrium dissociation constant (Kd) of its antagonist, H-3 QNB. Receptor autoradiography with high spatial resolution allowed the comparison of Bmax and Kd in the brain. To improve conventional Scatchard analysis, used in the estimation of Bmax and Kd, a new mathematical method was developed for estimating individual rate constants and Bmax on the basis of time courses of association and dissociation. Using the new mathematical method, apparent equilibrium dissociation rate constant was in good agreement with that from a non-isomerization model. Autoradiography may provide a clue for the basic data on brain receptor mapping by a promising emission computerized tomography in neuropsychiatric diseases. (Namekawa, K.).

  5. Autoradiographic localization of drug and neurotransmitter receptors in the brain

    International Nuclear Information System (INIS)

    Kuhar, M.J.

    1981-01-01

    By combining and adapting various methodologies, it is possible to develop radiohistochemical methods for the light microscopic localization of drug and neurotransmitter receptors in the brain. These methods are valuable complements to other histochemical methods for mapping neurotransmitters; they provide a unique view of neuroanatomy and they can be used to provide valuable new hypotheses about how drugs produce various effects. Interesting 'hot spots' of receptor localizations have been observed in some sensory and limbic areas of the brain. Because most available methods are light microscopic, the development of ultrastructural methods will be a necessary and important extension of this field. (Auth.)

  6. Mapping the calcitonin receptor in human brain stem

    DEFF Research Database (Denmark)

    Bower, Rebekah L; Eftekhari, Sajedeh; Waldvogel, Henry J

    2016-01-01

    understanding of these hormone systems by mapping CTR expression in the human brain stem, specifically the medulla oblongata. Widespread CTR-like immunoreactivity was observed throughout the medulla. Dense CTR staining was noted in several discrete nuclei, including the nucleus of the solitary tract...... receptors (AMY) are a heterodimer formed by the coexpression of CTR with receptor activity-modifying proteins (RAMPs). CTR with RAMP1 responds potently to both amylin and CGRP. The brain stem is a major site of action for circulating amylin and is a rich site of CGRP binding. This study aimed to enhance our...

  7. Mu opioid receptor binding sites in human brain

    International Nuclear Information System (INIS)

    Pilapil, C.; Welner, S.; Magnan, J.; Zamir, N.; Quirion, R.

    1986-01-01

    Our experiments focused on the examination of the distribution of mu opioid receptor binding sites in normal human brain using the highly selective ligand [ 3 H]DAGO, in both membrane binding assay and in vitro receptor autoradiography. Mu opioid binding sites are very discretely distributed in human brain with high densities of sites found in the posterior amygdala, caudate, putamen, hypothalamus and certain cortical areas. Moreover the autoradiographic distribution of [ 3 H]DAGO binding sites clearly reveals the discrete lamination (layers I and III-IV) of mu sites in cortical areas

  8. Receptor-Mediated Endocytosis and Brain Delivery of Therapeutic Biologics

    Directory of Open Access Journals (Sweden)

    Guangqing Xiao

    2013-01-01

    Full Text Available Transport of macromolecules across the blood-brain-barrier (BBB requires both specific and nonspecific interactions between macromolecules and proteins/receptors expressed on the luminal and/or the abluminal surfaces of the brain capillary endothelial cells. Endocytosis and transcytosis play important roles in the distribution of macromolecules. Due to the tight junction of BBB, brain delivery of traditional therapeutic proteins with large molecular weight is generally not possible. There are multiple pathways through which macromolecules can be taken up into cells through both specific and nonspecific interactions with proteins/receptors on the cell surface. This review is focused on the current knowledge of receptor-mediated endocytosis/transcytosis and brain delivery using the Angiopep-2-conjugated system and the molecular Trojan horses. In addition, the role of neonatal Fc receptor (FcRn in regulating the efflux of Immunoglobulin G (IgG from brain to blood, and approaches to improve the pharmacokinetics of therapeutic biologics by generating Fc fusion proteins, and increasing the pH dependent binding affinity between Fc and FcRn, are discussed.

  9. The distribution of multiple opiate receptors in bovine brain

    International Nuclear Information System (INIS)

    Ninkovic, M.; Hunt, S.P.; Emson, P.C.; Iversen, L.L.

    1981-01-01

    The distribution of μ and delta opiate receptors in bovine brain has been investigated using the selective radioligands [ 3 H]morphine and D-[ 3 H]Ala 2 , D-Leu 5 -enkephalin. Their distributions were found to vary independently through different brain areas with up to a 10-fold difference between the ratio of μ to delta binding sites for the substantia nigra and the dentate gyrus of the hippocampus. (Auth.)

  10. Oxytocin and Estrogen Receptor β in the Brain: An Overview

    OpenAIRE

    Acevedo-Rodriguez, Alexandra; Mani, Shaila K.; Handa, Robert J.

    2015-01-01

    Oxytocin is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release oxytocin into the bloodstream to promote labor and lactation; however, oxytocin neurons also project to other brain areas where it plays a role in numerous brain functions. Oxytocin binds to the widely expressed oxytocin receptor, and, in doing so, it regulates homeostatic processes, social ...

  11. Selective estrogen receptor modulators as brain therapeutic agents

    OpenAIRE

    Arévalo, María Ángeles; Santos-Galindo, María; Lagunas, Natalia; Azcoitia, I.; García-Segura, Luis M.

    2011-01-01

    Selective estrogen receptor modulators (SERMs), used for the treatment of breast cancer, osteoporosis, and menopausal symptoms, affect the nervous system. Some SERMs trigger neuroprotective mechanisms and reduce neural damage in different experimental models of neural trauma, brain inflammation, neurodegenerative diseases, cognitive impairment, and affective disorders. New SERMs with specific actions on neurons and glial cells may represent promising therapeutic tools for the brain. © 2011 So...

  12. Profiling neurotransmitter receptor expression in the Ambystoma mexicanum brain.

    Science.gov (United States)

    Reyes-Ruiz, Jorge Mauricio; Limon, Agenor; Korn, Matthew J; Nakamura, Paul A; Shirkey, Nicole J; Wong, Jamie K; Miledi, Ricardo

    2013-03-22

    Ability to regenerate limbs and central nervous system (CNS) is unique to few vertebrates, most notably the axolotl (Ambystoma sp.). However, despite the fact the neurotransmitter receptors are involved in axonal regeneration, little is known regarding its expression profile. In this project, RT-PCR and qPCR were performed to gain insight into the neurotransmitter receptors present in Ambystoma. Its functional ability was studied by expressing axolotl receptors in Xenopus laevis oocytes by either injection of mRNA or by direct microtransplantation of brain membranes. Oocytes injected with axolotl mRNA expressed ionotropic receptors activated by GABA, aspartate+glycine and kainate, as well as metabotropic receptors activated by acetylcholine and glutamate. Interestingly, we did not see responses following the application of serotonin. Membranes from the axolotl brain were efficiently microtransplanted into Xenopus oocytes and two types of native GABA receptors that differed in the temporal course of their responses and affinities to GABA were observed. Results of this study are necessary for further characterization of axolotl neurotransmitter receptors and may be useful for guiding experiments aimed at understanding activity-dependant limb and CNS regeneration. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. Adrenergic receptors in frontal cortex in human brain.

    Science.gov (United States)

    Cash, R; Raisman, R; Ruberg, M; Agid, Y

    1985-02-05

    The binding of three adrenergic ligands ([3H]prazosin, [3H]clonidine, [3H]dihydroalprenolol) was studied in the frontal cortex of human brain. alpha 1-Receptors, labeled by [3H]prazosin, predominated. [3H]Clonidine bound to two classes of sites, one of high affinity and one of low affinity. Guanosine triphosphate appeared to lower the affinity of [3H]clonidine for its receptor. [3H]Dihydroalprenolol bound to three classes of sites: the beta 1-receptor, the beta 2-receptor and a receptor with low affinity which represented about 40% of the total binding, but which was probably a non-specific site; the beta 1/beta 2 ratio was 1/2.

  14. Dopamine receptors in the Parkinsonian brain

    Energy Technology Data Exchange (ETDEWEB)

    Rinne, U K; Loennberg, P; Koskinen, V [Turku Univ. (Finland). Dept. of Neurology

    1981-01-01

    Striatal dopamine receptors were studied in 44 patients with Parkinson disease by the radioligand-binding technique using /sup 3/H-spiroperidol. The specific binding of /sup 3/H-spiroperidol was either significantly increased or reduced in the caudate nucleus and putamen of parkinsonian patients without levodopa therapy. Scatchard analysis showed that there were corresponding changes in the receptor number, but no significant changes in the mean dissociation constant. The increased binding of /sup 3/H-spiroperidol in the basal ganglia was also found in parkinsonian patients suffering from psychotic episodes and treated with neuroleptic drugs. Normal and low binding of /sup 3/H-spiroperidol was found in patients treated with levodopa. Clinically, the patient with low binding were more disabled and had lost the beneficial response to levodopa. Thus in Parkinson disease in some patients a denervation supersensitivity seemed to develop and in some others a loss of postsynaptic dopamine receptor sites in the neostriatium. The latter alteration may contribute to the decreased response of parkinsonian patients to chronic levodopa therapy.

  15. Dopamine receptors in the Parkinsonian brain

    International Nuclear Information System (INIS)

    Rinne, U.K.; Loennberg, P.; Koskinen, V.

    1981-01-01

    Striatal dopamine receptors were studied in 44 patients with Parkinson disease by the radioligand-binding technique using 3 H-spiroperidol. The specific binding of 3 H-spiroperidol was either significantly increased or reduced in the caudate nucleus and putamen of parkinsonian patients without levodopa therapy. Scatchard analysis showed that there were corresponding changes in the receptor number, but no significant changes in the mean dissociation constant. The increased binding of 3 H-spiroperidol in the basal ganglia was also found in parkinsonian patients suffering from psychotic episodes and treated with neuroleptic drugs. Normal and low binding of 3 H-spiroperidol was found in patients treated with levodopa. Clinically, the patient with low binding were more disabled and had lost the beneficial response to levodopa. Thus in Parkinson disease in some patients a denervation supersensitivity seemed to develop and in some others a loss of postsynaptic dopamine receptor sites in the neostriatium. The latter alteration may contribute to the decreased response of parkinsonian patients to chronic levodopa therapy. (author)

  16. The role of insulin receptor signaling in the brain.

    Science.gov (United States)

    Plum, Leona; Schubert, Markus; Brüning, Jens C

    2005-03-01

    The insulin receptor (IR) is expressed in various regions of the developing and adult brain, and its functions have become the focus of recent research. Insulin enters the central nervous system (CNS) through the blood-brain barrier by receptor-mediated transport to regulate food intake, sympathetic activity and peripheral insulin action through the inhibition of hepatic gluconeogenesis and reproductive endocrinology. On a molecular level, some of the effects of insulin converge with those of the leptin signaling machinery at the point of activation of phosphatidylinositol 3-kinase (PI3K), resulting in the regulation of ATP-dependent potassium channels. Furthermore, insulin inhibits neuronal apoptosis via activation of protein kinase B in vitro, and it regulates phosphorylation of tau, metabolism of the amyloid precursor protein and clearance of beta-amyloid from the brain in vivo. These findings indicate that neuronal IR signaling has a direct role in the link between energy homeostasis, reproduction and the development of neurodegenerative diseases.

  17. The vasopressin receptor of the blood-brain barrier in the rat hippocampus is linked to calcium signalling

    DEFF Research Database (Denmark)

    Hess, J.; Jensen, Claus V.; Diemer, Nils Henrik

    1991-01-01

    Neuropathology, vasopressin receptor, VI subtype, blood-brain barrier, cerebral endothelium, hippocampus, Fura-2......Neuropathology, vasopressin receptor, VI subtype, blood-brain barrier, cerebral endothelium, hippocampus, Fura-2...

  18. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    International Nuclear Information System (INIS)

    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-01-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of [ 3 H]Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in [14C]iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress [an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures], although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results

  19. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-06-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of (/sup 3/H)Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in (14C)iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress (an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures), although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results.

  20. Cyto- and receptor architectonic mapping of the human brain.

    Science.gov (United States)

    Palomero-Gallagher, Nicola; Zilles, Karl

    2018-01-01

    Mapping of the human brain is more than the generation of an atlas-based parcellation of brain regions using histologic or histochemical criteria. It is the attempt to provide a topographically informed model of the structural and functional organization of the brain. To achieve this goal a multimodal atlas of the detailed microscopic and neurochemical structure of the brain must be registered to a stereotaxic reference space or brain, which also serves as reference for topographic assignment of functional data, e.g., functional magnet resonance imaging, electroencephalography, or magnetoencephalography, as well as metabolic imaging, e.g., positron emission tomography. Although classic maps remain pioneering steps, they do not match recent concepts of the functional organization in many regions, and suffer from methodic drawbacks. This chapter provides a summary of the recent status of human brain mapping, which is based on multimodal approaches integrating results of quantitative cyto- and receptor architectonic studies with focus on the cerebral cortex in a widely used reference brain. Descriptions of the methods for observer-independent and statistically testable cytoarchitectonic parcellations, quantitative multireceptor mapping, and registration to the reference brain, including the concept of probability maps and a toolbox for using the maps in functional neuroimaging studies, are provided. Copyright © 2018 Elsevier B.V. All rights reserved.

  1. Characterization of melanocortin receptor ligands on cloned brain melanocortin receptors and on grooming behavior in the rat

    NARCIS (Netherlands)

    Gispen, W.H.; Adan, R.A.H.; Szklarczyk, A.W.; Oosterom, J.; Brakkee, J.H.; Nijenhuis, W.A.; Schaaper, W.M.; Meloen, R.H.

    1999-01-01

    Since the melanocortin MC3 and melanocortin MC4 receptors are the main melanocortin receptor subtypes expressed in rat brain, we characterized the activity and affinity of nine melanocortin receptor ligands using these receptors in vitro, as well as their activity in a well-defined

  2. In vivo study of drug interaction with brain benzodiazepine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, O.; Shinotoh, H.; Ito, T.; Suzuki, K.; Hashimoto, K.; Yamasaki, T.

    1985-05-01

    The possibility of direct estimation of in vivo Bz receptor occupancy in brain was evaluated using C-11, or H-3-flumazepil (Ro15-1788). In animal experiments, 1 ..mu..Ci of H-3-Ro15-1788 was injected at 0.5 or 20 hr after i.v. injection of various dosage of clonazepam. Then radioactivity in cerebral cortex, cerebellum and blood at 5 min. after injection of the tracer was compared. Competitive inhibition of in vivo binding was clearly observed when clonazepam was pretreated at 0.5 hr before injection of the tracer. On the other hand, brain radioactivity was increased when clonazepam was administered at 20 hr before injection of the tracer. This increase in binding of H-3-Ro15-1788 might be caused by rebound of Bz receptor function by treatment with Bz agonist, and this rebound may have an important role in physiological function. Clinical investigation concerning drug interaction with brain Bz receptor was performed in normal volunteer and patients with neurological disorders. The distribution of C-11-Ro15-1788 in the brain of patients chronically treated with clonazepam were significantly heterogeneous. However, cerebral blood flow estimated with N-13 NH3 of these patients were normal.

  3. Solubilization and purification of melatonin receptors from lizard brain

    International Nuclear Information System (INIS)

    Rivkees, S.A.; Conron, R.W. Jr.; Reppert, S.M.

    1990-01-01

    Melatonin receptors in lizard brain were identified and characterized using 125 I-labeled melatonin ([ 125 I]MEL) after solubilization with the detergent digitonin. Saturation studies of solubilized material revealed a high affinity binding site, with an apparent equilibrium dissociation constant of 181 +/- 45 pM. Binding was reversible and inhibited by melatonin and closely related analogs, but not by serotonin or norepinephrine. Treatment of solubilized material with the non-hydrolyzable GTP analog, guanosine 5'-(3-O-thiotriphosphate) (GTP-gamma-S), significantly reduced receptor affinity. Gel filtration chromatography of solubilized melatonin receptors revealed a high affinity, large (Mr 400,000) peak of specific binding. Pretreatment with GTP-gamma-S before solubilization resulted in elution of a lower affinity, smaller (Mr 150,000) peak of specific binding. To purify solubilized receptors, a novel affinity chromatography resin was developed by coupling 6-hydroxymelatonin with Epoxy-activated Sepharose 6B. Using this resin, melatonin receptors were purified approximately 10,000-fold. Purified material retained the pharmacologic specificity of melatonin receptors. These results show that melatonin receptors that bind ligand after detergent treatment can be solubilized and substantially purified by affinity chromatography

  4. Solubilization and purification of melatonin receptors from lizard brain.

    Science.gov (United States)

    Rivkees, S A; Conron, R W; Reppert, S M

    1990-09-01

    Melatonin receptors in lizard brain were identified and characterized using 125I-labeled melatonin ([125I]MEL) after solubilization with the detergent digitonin. Saturation studies of solubilized material revealed a high affinity binding site, with an apparent equilibrium dissociation constant of 181 +/- 45 pM. Binding was reversible and inhibited by melatonin and closely related analogs, but not by serotonin or norepinephrine. Treatment of solubilized material with the non-hydrolyzable GTP analog, guanosine 5'-(3-O-thiotriphosphate) (GTP-gamma-S), significantly reduced receptor affinity. Gel filtration chromatography of solubilized melatonin receptors revealed a high affinity, large (Mr 400,000) peak of specific binding. Pretreatment with GTP-gamma-S before solubilization resulted in elution of a lower affinity, smaller (Mr 150,000) peak of specific binding. To purify solubilized receptors, a novel affinity chromatography resin was developed by coupling 6-hydroxymelatonin with Epoxy-activated Sepharose 6B. Using this resin, melatonin receptors were purified approximately 10,000-fold. Purified material retained the pharmacologic specificity of melatonin receptors. These results show that melatonin receptors that bind ligand after detergent treatment can be solubilized and substantially purified by affinity chromatography.

  5. Communication networks in the brain: neurons, receptors, neurotransmitters, and alcohol.

    Science.gov (United States)

    Lovinger, David M

    2008-01-01

    Nerve cells (i.e., neurons) communicate via a combination of electrical and chemical signals. Within the neuron, electrical signals driven by charged particles allow rapid conduction from one end of the cell to the other. Communication between neurons occurs at tiny gaps called synapses, where specialized parts of the two cells (i.e., the presynaptic and postsynaptic neurons) come within nanometers of one another to allow for chemical transmission. The presynaptic neuron releases a chemical (i.e., a neurotransmitter) that is received by the postsynaptic neuron's specialized proteins called neurotransmitter receptors. The neurotransmitter molecules bind to the receptor proteins and alter postsynaptic neuronal function. Two types of neurotransmitter receptors exist-ligand-gated ion channels, which permit rapid ion flow directly across the outer cell membrane, and G-protein-coupled receptors, which set into motion chemical signaling events within the cell. Hundreds of molecules are known to act as neurotransmitters in the brain. Neuronal development and function also are affected by peptides known as neurotrophins and by steroid hormones. This article reviews the chemical nature, neuronal actions, receptor subtypes, and therapeutic roles of several transmitters, neurotrophins, and hormones. It focuses on neurotransmitters with important roles in acute and chronic alcohol effects on the brain, such as those that contribute to intoxication, tolerance, dependence, and neurotoxicity, as well as maintained alcohol drinking and addiction.

  6. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors

    International Nuclear Information System (INIS)

    Pazos, A.; Cortes, R.; Palacios, J.M.

    1985-01-01

    The distribution of serotonin-2 (5-HT 2 ) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with four ligands: [ 3 H]ketanserin, [ 3 H]mesulergine, [ 3 H]LSD and [ 3 H]spiperone, which are reported to show high affinity for 5-HT 2 receptors. Very high concentrations were localized in the claustrum, olfactory tubercle and layer IV of the neocortex. The anterior olfactory nucleus, piriform cortex and layer I of neocortex were also rich in 5-HT 2 receptors. The specificity of the different ligands used is discussed in terms of the other populations of sites recognized by them. The distribution of 5-HT 2 receptors here reported is discussed in correlation with (a) the known distribution of serotoninergic terminals, (b) the specific anatomical systems and (c) the central effects reported to be mediated by 5-HT 2 -selective drugs. (Auth.)

  7. Identification of rat brain opioid (enkephalin) receptor by photoaffinity labeling

    International Nuclear Information System (INIS)

    Yeung, C.W.

    1986-01-01

    A photoreactive, radioactive enkephalin derivative was prepared and purified by high performance liquid chromatography. Rat brain and spinal cord plasma membranes were incubated with this radioiodinated photoprobe and were subsequently photolysed. Autoradiography of the sodium dodecyl sulfate gel electrophoresis of the solubilized and reduced membranes showed that a protein having an apparent molecular weight of 46,000 daltons was specifically labeled, suggesting that this protein may be the opioid (enkephalin) receptor

  8. Presynaptic localization of histamine H3-receptors in rat brain

    International Nuclear Information System (INIS)

    Fujimoto, K.; Mizuguchi, H.; Fukui, H.; Wada, H.

    1991-01-01

    The localization of histamine H3-receptors in subcellular fractions from the rat brain was examined in a [3H] (R) alpha-methylhistamine binding assay and compared with those of histamine H1- and adrenaline alpha 1- and alpha 2-receptors. Major [3H](R) alpha-methylhistamine binding sites with increased specific activities ([3H]ligand binding vs. protein amount) were recovered from the P2 fraction by differential centrifugation. Minor [3H](R)alpha-methylhistamine binding sites with increased specific activities were also detected in the P3 fraction. Further subfractionation of the P2 fraction by discontinuous sucrose density gradient centrifugation showed major recoveries of [3H](R)alpha-methylhistamine binding in myelin (MYE) and synaptic plasma membrane (SPM) fractions. A further increase in specific activity was observed in the MYE fraction, but the SPM fraction showed no significant increase in specific activity. Adrenaline alpha 2-receptors, the pre-synaptic autoreceptors, in a [3H] yohimbine binding assay showed distribution patterns similar to histamine H3-receptors. On the other hand, post-synaptic histamine H1- and adrenaline alpha 1-receptors were closely localized and distributed mainly in the SPM fraction with increased specific activity. Only a negligible amount was recovered in the MYE fraction, unlike the histamine H3- and adrenaline alpha 2-receptors

  9. Sigma and opioid receptors in human brain tumors

    International Nuclear Information System (INIS)

    Thomas, G.E.; Szuecs, M.; Mamone, J.Y.; Bem, W.T.; Rush, M.D.; Johnson, F.E.; Coscia, C.J.

    1990-01-01

    Human brain tumors and nude mouse-borne human neuroblastomas and gliomas were analyzed for sigma and opioid receptor content. Sigma binding was assessed using [ 3 H] 1, 3-di-o-tolylguanidine (DTG), whereas opioid receptor subtypes were measured with tritiated forms of the following: μ, [D-ala 2 , mePhe 4 , gly-ol 5 ] enkephalin (DAMGE); κ, ethylketocyclazocine (EKC) or U69,593; δ, [D-pen 2 , D-pen 5 ] enkephalin (DPDPE) or [D-ala 2 , D-leu 5 ] enkephalin (DADLE) with μ suppressor present. Binding parameters were estimated by homologous displacement assays followed by analysis using the LIGAND program. Sigma binding was detected in 15 of 16 tumors examined with very high levels found in a brain metastasis from an adenocarcinoma of lung and a human neuroblastoma (SK-N-MC) passaged in nude mice. κ opioid receptor binding was detected in 4 of 4 glioblastoma multiforme specimens and 2 of 2 human astrocytoma cell lines tested but not in the other brain tumors analyzed

  10. Sigma and opioid receptors in human brain tumors

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G.E.; Szuecs, M.; Mamone, J.Y.; Bem, W.T.; Rush, M.D.; Johnson, F.E.; Coscia, C.J. (St. Louis Univ. School of Medicine, MO (USA))

    1990-01-01

    Human brain tumors and nude mouse-borne human neuroblastomas and gliomas were analyzed for sigma and opioid receptor content. Sigma binding was assessed using ({sup 3}H) 1, 3-di-o-tolylguanidine (DTG), whereas opioid receptor subtypes were measured with tritiated forms of the following: {mu}, (D-ala{sup 2}, mePhe{sup 4}, gly-ol{sup 5}) enkephalin (DAMGE); {kappa}, ethylketocyclazocine (EKC) or U69,593; {delta}, (D-pen{sup 2}, D-pen{sup 5}) enkephalin (DPDPE) or (D-ala{sup 2}, D-leu{sup 5}) enkephalin (DADLE) with {mu} suppressor present. Binding parameters were estimated by homologous displacement assays followed by analysis using the LIGAND program. Sigma binding was detected in 15 of 16 tumors examined with very high levels found in a brain metastasis from an adenocarcinoma of lung and a human neuroblastoma (SK-N-MC) passaged in nude mice. {kappa} opioid receptor binding was detected in 4 of 4 glioblastoma multiforme specimens and 2 of 2 human astrocytoma cell lines tested but not in the other brain tumors analyzed.

  11. Effects of antidepressant drugs on different receptors in the brain

    International Nuclear Information System (INIS)

    Hall, H.; Oegren, S.-O.

    1981-01-01

    Radioligand receptor binding techniques were used to characterize the effects of different structural types of antidepressant drugs on neurotransmitter receptors. The tricyclic antidepressants more or less potently inhibited the binding to rat brain preparations of several different radiolabelled ligands ([ 3 H]WB4101, [ 3 H]QNB, [ 3 H]d-LSD, [ 3 H]mepyramine). The potency of the nontricyclic antidepressants varied greatly. Mianserin, potently displaced [ 3 H]mepyramine, [ 3 H]d-LSD and [ 3 H]WB4101 while it was very weak on [ 3 H]QNB-binding. Nomifensine and the specific 5-HT uptake inhibitors zimelidine and alaproclate had very low affinity for these receptors. All the antidepressants tested were practically devoid of activity on [ 3 H]DHA binding, [ 3 H]spiroperidol binding, [ 3 H]flunitrazepam binding, [ 3 H]muscimol binding and [ 3 H]naloxone binding. The implications of these findings for biogenic amine theories of affective disorders are discussed. (Auth.)

  12. Sex Differences in Serotonin 1 Receptor Binding in Rat Brain

    Science.gov (United States)

    Fischette, Christine T.; Biegon, Anat; McEwen, Bruce S.

    1983-10-01

    Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

  13. Oxytocin and Estrogen Receptor β in the Brain: An Overview

    Directory of Open Access Journals (Sweden)

    Alexandra eAcevedo-Rodriguez

    2015-10-01

    Full Text Available Oxytocin is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release oxytocin into the bloodstream to promote labor and lactation; however, oxytocin neurons also project to other brain areas where it plays a role in numerous brain functions. Oxytocin binds to the widely expressed oxytocin receptor, and, in doing so, it regulates homeostatic processes, social recognition and fear conditioning. In addition to these functions, oxytocin decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter oxytocin receptor expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase oxytocin peptide transcription, suggesting a role for oxytocin in this estrogen receptor β mediated anxiolytic effect. Further research is needed to identify modulators of oxytocin signaling and the pathways utilized and to elucidate molecular mechanisms controlling oxytocin expression to allow better therapeutic manipulations of this system in patient populations.

  14. Quantitative autoradiography of [3H]corticosterone receptors in rat brain

    International Nuclear Information System (INIS)

    Sapolsky, R.M.; McEwen, B.S.; Rainbow, T.C.

    1983-01-01

    The authors have quantified corticosterone receptors in rat brain by optical density measurements of tritium-film autoradiograms. Rats were injected i.v. with 500 μCi [ 3 H]corticosterone to label brain receptors. Frozen sections of brain were cut with a cryostat and exposed for 2 months against tritium-sensitive sheet film (LKB Ultrofilm). Tritium standards were used to convert optical density readings into molar concentrations of receptor. High levels of corticosterone receptors were present throughout the pyramidal and granule cell layers of the hippocampus. Moderate levels of receptors were found in the neuropil of the hippocampus, the lateral septum, the cortical nucleus of the amygdala and the entorhinal cortex. All other brain regions had low levels of receptors. These results extend previous non-quantitative autoradigraphic studies of corticosterone receptors and provide a general procedure for the quantitative autoradiography of steroid hormone receptors in brain tissue. (Auth.)

  15. Decreased Brain Neurokinin-1 Receptor Availability in Chronic Tennis Elbow.

    Science.gov (United States)

    Linnman, Clas; Catana, Ciprian; Svärdsudd, Kurt; Appel, Lieuwe; Engler, Henry; Långström, Bengt; Sörensen, Jens; Furmark, Tomas; Fredrikson, Mats; Borsook, David; Peterson, Magnus

    Substance P is released in painful and inflammatory conditions, affecting both peripheral processes and the central nervous system neurokinin 1 (NK1) receptor. There is a paucity of data on human brain alterations in NK1 expression, how this system may be affected by treatment, and interactions between central and peripheral tissue alterations. Ten subjects with chronic tennis elbow (lateral epicondylosis) were selected out of a larger (n = 120) randomized controlled trial evaluating graded exercise as a treatment for chronic tennis elbow (lateral epicondylosis). These ten subjects were examined by positron emission tomography (PET) with the NK1-specific radioligand 11C-GR205171 before, and eight patients were followed up after treatment with graded exercise. Brain binding in the ten patients before treatment, reflecting NK1-receptor availability (NK1-RA), was compared to that of 18 healthy subjects and, longitudinally, to the eight of the original ten patients that agreed to a second PET examination after treatment. Before treatment, patients had significantly lower NK1-RA in the insula, vmPFC, postcentral gyrus, anterior cingulate, caudate, putamen, amygdala and the midbrain but not the thalamus and cerebellum, with the largest difference in the insula contralateral to the injured elbow. No significant correlations between brain NK1-RA and pain, functional severity, or peripheral NK1-RA in the affected limb were observed. In the eight patients examined after treatment, pain ratings decreased in everyone, but there were no significant changes in NK1-RA. These findings indicate a role for the substance P (SP) / NK1 receptor system in musculoskeletal pain and tissue healing. As neither clinical parameters nor successful treatment response was reflected in brain NK1-RA after treatment, this may reflect the diverse function of the SP/NK1 system in CNS and peripheral tissue, or a change too small or slow to capture over the three-month treatment.

  16. Decreased Brain Neurokinin-1 Receptor Availability in Chronic Tennis Elbow.

    Directory of Open Access Journals (Sweden)

    Clas Linnman

    Full Text Available Substance P is released in painful and inflammatory conditions, affecting both peripheral processes and the central nervous system neurokinin 1 (NK1 receptor. There is a paucity of data on human brain alterations in NK1 expression, how this system may be affected by treatment, and interactions between central and peripheral tissue alterations. Ten subjects with chronic tennis elbow (lateral epicondylosis were selected out of a larger (n = 120 randomized controlled trial evaluating graded exercise as a treatment for chronic tennis elbow (lateral epicondylosis. These ten subjects were examined by positron emission tomography (PET with the NK1-specific radioligand 11C-GR205171 before, and eight patients were followed up after treatment with graded exercise. Brain binding in the ten patients before treatment, reflecting NK1-receptor availability (NK1-RA, was compared to that of 18 healthy subjects and, longitudinally, to the eight of the original ten patients that agreed to a second PET examination after treatment. Before treatment, patients had significantly lower NK1-RA in the insula, vmPFC, postcentral gyrus, anterior cingulate, caudate, putamen, amygdala and the midbrain but not the thalamus and cerebellum, with the largest difference in the insula contralateral to the injured elbow. No significant correlations between brain NK1-RA and pain, functional severity, or peripheral NK1-RA in the affected limb were observed. In the eight patients examined after treatment, pain ratings decreased in everyone, but there were no significant changes in NK1-RA. These findings indicate a role for the substance P (SP / NK1 receptor system in musculoskeletal pain and tissue healing. As neither clinical parameters nor successful treatment response was reflected in brain NK1-RA after treatment, this may reflect the diverse function of the SP/NK1 system in CNS and peripheral tissue, or a change too small or slow to capture over the three-month treatment.

  17. Oxytocin and Estrogen Receptor β in the Brain: An Overview.

    Science.gov (United States)

    Acevedo-Rodriguez, Alexandra; Mani, Shaila K; Handa, Robert J

    2015-01-01

    Oxytocin (OT) is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release OT into the bloodstream to promote labor and lactation; however, OT neurons also project to other brain areas where it plays a role in numerous brain functions. OT binds to the widely expressed OT receptor (OTR), and, in doing so, it regulates homeostatic processes, social recognition, and fear conditioning. In addition to these functions, OT decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter OTR expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase OT peptide transcription, suggesting a role for OT in this estrogen receptor β-mediated anxiolytic effect. Further research is needed to identify modulators of OT signaling and the pathways utilized and to elucidate molecular mechanisms controlling OT expression to allow better therapeutic manipulations of this system in patient populations.

  18. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors

    International Nuclear Information System (INIS)

    Pazos, A.; Palacios, M.

    1985-01-01

    The distribution of serotonin-1 (5-HT 1 ) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with [ 3 H]serotonin (5-[ 3 H]HT), 8-hydroxy-2-[N-dipropylamino- 3 H]tetralin (8-OH-[ 3 H]DPAT), [ 3 H]LSD and [ 3 H]mesulergine, and the densities quantified by microdensitometry with the aid of a computer-assisted image-analysis system. Competition experiments for 5-[ 3 H]HT binding by several serotonin-1 agonists led to the identification of brain areas enriched in each one of the three subtypes of 5-HT 1 recognition sites already described. The existence of these 'selective' areas allowed a detailed pharmacological characterization of these sites to be made in a more precise manner than has been attained in membrane-binding studies. Very high concentrations of 5-HT 1 receptors were localized in the choroid plexus, lateroseptal nucleus, globus pallidus and ventral pallidum, dentate gyrus, dorsal subiculum, olivary pretectal nucleus, substantia nigra, reticular and external layer of the entorhinal cortex. The distribution of 5-HT 1 receptors reported here is discussed in correlation with the distribution of serotoninergic neurons and fibers, the related anatomical pathways and the effects which appear to be mediated by these sites. (Auth.)

  19. Relationship between changes of N-methyl-D-aspartate receptor activity and brain edema after brain injury in rats

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To investigate the relationship between the changes of N-methyl-D-aspartate (NMDA) receptor activity and brain edema after injury in rats.   Methods: The brain injury models were made by using a free-falling body. The treatment model was induced by means of injecting AP5 into lateral ventricle before brain injury; water contents in brain cortex were measured with dry-wet method; and NMDA receptor activity was detected with a radio ligand binding assay.   Results: The water contents began to increase at 30 minutes and reached the peak at 6 hours after brain injury. The maximal binding (Bmax) of NMDA receptor increased significantly at 15 minutes and reached the peak at 30 minutes, then decreased gradually and had the lowest value 6 hours after brain injury. Followed the treatment with AP5, NMDA receptor activity in the injured brain showed a normal value; and the water contents were lower than that of AP5-free injury group 24 hours after brain injury.   Conclusions: It suggests that excessive activation of NMDA receptor may be one of the most important factors to induce the secondary cerebral impairments, and AP5 may protect the brain from edema after brain injury.

  20. The effect of infectious brain edema on NMDA receptor binding in rat's brain

    International Nuclear Information System (INIS)

    Cheng Guansheng; Chen Jianfang; Chen Xiang

    1997-01-01

    PURPOSE: The effect of the infectious brain edema (IBE) induced by Bordetella Pertussis (BP) on the specific binding of 3 H MK-801 in rat's brain in vivo was determined. METHODS: BP was injected via left internal carotid artery in rat model of infectious brain edema. Male SD rats were divided into three groups: 1) Group control (NS, n = 11); 2) Group IBF (BP, n = 12); 3) Group pretreatment of MK-801 + PB (MK-801, n = 4). Normal saline or BP 0.2 ml/kg was injected into left internal carotid artery in NS and BP group respectively. MK-801 0.5 mg/kg per day was injected i.p. two days before injection of BP in group MK-801. Rats were killed by decapitation at 24 hours after injection of BP. The specific binding of N-methyl-D-aspartate (NMDA) receptor were measured with 3 H-MK-801 in the neuronal membrane of cerebral cortex. The Scatchard plots were performed. RESULTS: The B max values were 0.623 +- 0.082 and 0.606 +- 0.087 pmol/mg protein in group NS and BP respectively (t = 0.48, P>0.05). The Kd values were 43.1 +- 4.2 and 30.5 +- 3.0 nmol/L in group NS and BP respectively (t = 7.8, P<0.05). The specific binding of NMDA receptor was decreased by pretreatment of MK-801. CONCLUSIONS: The total number of NMDA receptor had not changed, whereas its affinity increased significantly in the model of brain edema induced by pertussis bacilli in rat. The increase of affinity of NMDA receptor can be blockaded by MK-801 pretreatment in vivo

  1. Cognitive disorder and changes in cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury

    Institute of Scientific and Technical Information of China (English)

    Weiliang Zhao; Dezhi Kang; Yuanxiang Lin

    2008-01-01

    BACKGROUND: Learning and memory damage is one of the most permanent and the severest symptoms of traumatic brain injury; it can seriously influence the normal life and work of patients. Some research has demonstrated that cognitive disorder is closely related to nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor. OBJECTIVE: To summarize the cognitive disorder and changes in nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury. RETRIEVAL STRATEGY: A computer-based online search was conducted in PUBMED for English language publications containing the key words "brain injured, cognitive handicap, acetylcholine, N-methyl-D aspartate receptors, neural cell adhesion molecule, brain-derived neurotrophic factor" from January 2000 to December 2007. There were 44 papers in total. Inclusion criteria: ① articles about changes in nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury; ② articles in the same researching circle published in authoritative journals or recently published. Exclusion criteria: duplicated articles.LITERATURE EVALUATION: References were mainly derived from research on changes in these four factors following brain injury. The 20 included papers were clinical or basic experimental studies. DATA SYNTHESIS: After craniocerebral injury, changes in these four factors in brain were similar to those during recovery from cognitive disorder, to a certain degree. Some data have indicated that activation of nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor could greatly improve cognitive disorder following brain injury. However, there are still a lot of questions remaining; for example, how do these

  2. Serotonin and brain function: a tale of two receptors.

    Science.gov (United States)

    Carhart-Harris, R L; Nutt, D J

    2017-09-01

    Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

  3. Kappa opioid receptors stimulate phosphoinositide turnover in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Periyasamy, S.; Hoss, W. (Univ. of Toledo, OH (USA))

    1990-01-01

    The effects of various subtype-selective opioid agonists and antagonists on the phosphoinositide (PI) turnover response were investigated in the rat brain. The {kappa}-agonists U-50,488H and ketocyclazocine produced a concentration-dependent increase in the accumulation of IP's in hippocampal slices. The other {kappa}-agonists Dynorphin-A (1-13) amide, and its protected analog D(Ala){sup 2}-dynorphin-A (1-13) amide also produced a significant increase in the formation of ({sup 3}H)-IP's, whereas the {mu}-selective agonists (D-Ala{sup 2}-N-Me-Phe{sup 4}-Gly{sup 5}-ol)-enkephalin and morphine and the {delta}-selective agonist (D-Pen{sup 2,5})-enkephalin were ineffective. The increase in IP's formation elicited by U-50,488H was partially antagonized by naloxone and more completely antagonized by the {kappa}-selective antagonists nor-binaltorphimine and MR 2266. The formation of IP's induced by U-50,488H varies with the regions of the brain used, being highest in hippocampus and amygdala, and lowest in striatum and pons-medullar. The results indicate that brain {kappa}- but neither {mu}- nor {delta}- receptors are coupled to the PI turnover response.

  4. Interleukin-1 receptors in mouse brain: Characterization and neuronal localization

    International Nuclear Information System (INIS)

    Takao, T.; Tracey, D.E.; Mitchell, W.M.; De Souza, E.B.

    1990-01-01

    The cytokine interleukin-1 (IL-1) has a variety of effects in brain, including induction of fever, alteration of slow wave sleep, and alteration of neuroendocrine activity. To examine the potential sites of action of IL-1 in brain, we used iodine-125-labeled recombinant human interleukin-1 [( 125I]IL-1) to identify and characterize IL-1 receptors in crude membrane preparations of mouse (C57BL/6) hippocampus and to study the distribution of IL-1-binding sites in brain using autoradiography. In preliminary homogenate binding and autoradiographic studies, [125I]IL-1 alpha showed significantly higher specific binding than [125I]IL-1 beta. Thus, [125I]IL-1 alpha was used in all subsequent assays. The binding of [125I]IL-1 alpha was linear over a broad range of membrane protein concentrations, saturable, reversible, and of high affinity, with an equilibrium dissociation constant value of 114 +/- 35 pM and a maximum number of binding sites of 2.5 +/- 0.4 fmol/mg protein. In competition studies, recombinant human IL-1 alpha, recombinant human IL-1 beta, and a weak IL-1 beta analog. IL-1 beta +, inhibited [125I]IL-1 alpha binding to mouse hippocampus in parallel with their relative bioactivities in the T-cell comitogenesis assay, with inhibitory binding affinity constants of 55 +/- 18, 76 +/- 20, and 2940 +/- 742 pM, respectively; rat/human CRF and human tumor necrosis factor showed no effect on [125I]IL-1 alpha binding. Autoradiographic localization studies revealed very low densities of [125I]IL-1 alpha-binding sites throughout the brain, with highest densities present in the molecular and granular layers of the dentate gyrus of the hippocampus and in the choroid plexus. Quinolinic acid lesion studies demonstrated that the [125I]IL-1 alpha-binding sites in the hippocampus were localized to intrinsic neurons

  5. Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

    DEFF Research Database (Denmark)

    Quintana, Albert; Giralt, Mercedes; Rojas, Santiago

    2005-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via intracell......Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via...... intracellular signaling. This cytokine exerts its functions via interaction with two receptors: type-1 receptor (TNFR1) and type-2 receptor (TNFR2). In this work, the inflammatory response after a freeze injury (cryolesion) in the cortex was studied in wild-type (WT) animals and in mice lacking TNFR1 (TNFR1 KO...... signaling also affected the expression of apoptosis/cell death-related genes (Fas, Rip, p53), matrix metalloproteinases (MMP3, MMP9, MMP12), and their inhibitors (TIMP1), suggesting a role of TNFR1 in extracellular matrix remodeling after injury. However, GDNF, NGF, and BDNF expression were not affected...

  6. Leptin Receptor Deficiency is Associated With Upregulation of Cannabinoid 1 Receptors in Limbic Brain Regions

    Science.gov (United States)

    THANOS, PANAYOTIS K.; RAMALHETE, ROBERTO C.; MICHAELIDES, MICHAEL; PIYIS, YIANNI K.; WANG, GENE-JACK; VOLKOW, NORA D.

    2009-01-01

    Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB1R) in overeating and the effects of food deprivation on CB1R in the brain. One-month-old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB1R (CB1R binding levels) were assessed using [3H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB1R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB1R binding levels than Le in most brain regions and food restriction was associated with higher CB1R levels in all brain regions in Ob, but not in Le rats. CB1R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB1R in Ob rats suggest that leptin's inhibition of food-intake is in part mediated by downregulation of CB1R and that leptin interferes with CB1R upregulation under food-deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin. PMID:18563836

  7. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers

    OpenAIRE

    Hirvonen, J; Goodwin, RS; Li, C-T; Terry, GE; Zoghbi, SS; Morse, C; Pike, VW; Volkow, ND; Huestis, MA; Innis, RB

    2011-01-01

    Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB1 (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke ca...

  8. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers.

    Science.gov (United States)

    Hirvonen, J; Goodwin, R S; Li, C-T; Terry, G E; Zoghbi, S S; Morse, C; Pike, V W; Volkow, N D; Huestis, M A; Innis, R B

    2012-06-01

    Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB(1) (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB(1) receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ∼4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB(1) receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB(1) receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.

  9. Comparison between narcotic 'receptors' in the guinea-pig ileum and the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Terenius, L [Uppsala Univ. (Sweden)

    1975-01-01

    The receptors, i.e., specific binding molecules, for narcotic analgesics in the guinea-pig ileum and rat brain have been compared. The relative affinities of a number of narcotics for the two receptors were very similar and discrimination between stereoisomeric agents was identical. The dissociation constants for dihydromorphine binding were 0.78 nM for the ileum and 1.4 nM for the brain receptor, respectively. There was a good correspondance between receptor affinities on the ileum preparation and the literature data on biologic activity on the isolated ileum. Codeine, diphenoxylate, difenoxine and loperamide, which are used clinically for the treatment of diarrhoea showed no selectivity against the ileum receptor. The two latter drugs had a very high receptor affinity and their lack of narcotic activity after oral administration is probably attributable to lack of penetration of the CNS. Receptor binding in both ileum and brain preparations was inhibited by N-ethylmaleimide, Triton X-100, trypsin and phospholipase C. There were small quantitative differences in sensitivity to these agents but it is difficult to assess whether this is because of real differences between the receptor molecules or attributable to secondary effects. As previously described for the brain receptor, the ileum receptor appeared to be present in a fraction enriched in plasma membranes.

  10. Autoradiographic analysis of alpha 1-noradrenergic receptors in the human brain postmortem. Effect of suicide

    International Nuclear Information System (INIS)

    Gross-Isseroff, R.; Dillon, K.A.; Fieldust, S.J.; Biegon, A.

    1990-01-01

    In vitro quantitative autoradiography of alpha 1-noradrenergic receptors, using tritiated prazosin as a ligand, was performed on 24 human brains postmortem. Twelve brains were obtained from suicide victims and 12 from matched controls. We found significant lower binding to alpha 1 receptors in several brain regions of the suicide group as compared with matched controls. This decrease in receptor density was evident in portions of the prefrontal cortex, as well as the temporal cortex and in the caudate nucleus. Age, sex, presence of alcohol, and time of death to autopsy did not affect prazosin binding, in our sample, as measured by autoradiography

  11. The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke

    DEFF Research Database (Denmark)

    Ruscher, Karsten; Shamloo, Mehrdad; Rickhag, Karl Mattias

    2011-01-01

    Stroke leads to brain damage with subsequent slow and incomplete recovery of lost brain functions. Enriched housing of stroke-injured rats provides multi-modal sensorimotor stimulation, which improves recovery, although the specific mechanisms involved have not been identified. In rats housed in ...... of biomolecules required for brain repair, thereby stimulating brain plasticity. Pharmacological targeting of the sigma-1 receptor provides new opportunities for stroke treatment beyond the therapeutic window of neuroprotection....

  12. Decreased α1-adrenergic receptor-mediated inositide hydrolysis in neurons from hypertensive rat brain

    International Nuclear Information System (INIS)

    Feldstein, J.B.; Gonzales, R.A.; Baker, S.P.; Sumners, C.; Crews, F.T.; Raizada, M.K.

    1986-01-01

    The expression of α 1 -adrenergic receptors and norepinephrine (NE)-stimulated hydrolysis of inositol phospholipid has been studied in neuronal cultures from the brains of normotensive (Wistar-Kyoto, WKY) and spontaneously hypertensive (SH) rats. Binding of 125 I-1-[β-(4-hydroxyphenyl)-ethyl-aminomethyl] tetralone (HEAT) to neuronal membranes was 68-85% specific and was rapid. Competition-inhibition experiments with various agonists and antagonists suggested that 125 I-HEAT bound selectively to α 1 -adrenergic receptors. Specific binding of 125 I-HEAT to neuronal membranes from SH rat brain cultures was 30-45% higher compared with binding in WKY normotensive controls. This increase was attributed to an increase in the number of α 1 -adrenergic receptors on SH rat brain neurons. Incubation of neuronal cultures of rat brain from both strains with NE resulted in a concentration-dependent stimulation of release of inositol phosphates, although neurons from SH rat brains were 40% less responsive compared with WKY controls. The decrease in responsiveness of SH rat brain neurons to NE, even though the α 1 -adrenergic receptors are increased, does not appear to be due to a general defect in membrane receptors and postreceptor signal transduction mechanisms. This is because neither the number of muscarinic-cholinergic receptors nor the carbachol-stimulated release of inositol phosphates is different in neuronal cultures from the brains of SH rats compared with neuronal cultures from the brains of WKY rats. These observations suggest that the increased expression of α 1 -adrenergic receptors does not parallel the receptor-mediated inositol phosphate hydrolysis in neuronal cultures from SH rat brain

  13. Positron Emission Tomography (PET Quantification of GABAA Receptors in the Brain of Fragile X Patients.

    Directory of Open Access Journals (Sweden)

    Charlotte D'Hulst

    Full Text Available Over the last several years, evidence has accumulated that the GABAA receptor is compromised in animal models for fragile X syndrome (FXS, a common hereditary form of intellectual disability. In mouse and fly models, agonists of the GABAA receptor were able to rescue specific consequences of the fragile X mutation. Here, we imaged and quantified GABAA receptors in vivo in brain of fragile X patients using Positron Emission Topography (PET and [11C]flumazenil, a known high-affinity and specific ligand for the benzodiazepine site of GABAA receptors. We measured regional GABAA receptor availability in 10 fragile X patients and 10 control subjects. We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients. In the thalamus, the brain region showing the largest difference, the GABAA receptor availability was even reduced with 17%. This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABAA receptor availability is reduced in fragile X patients. The study reinforces previous hypotheses that the GABAA receptor is a potential target for rational pharmacological treatment of fragile X syndrome.

  14. Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma

    DEFF Research Database (Denmark)

    Johnsen, Kasper B.; Burkhart, Annette; Melander, Fredrik

    2017-01-01

    Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibi...... cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain....... investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor-targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does...... not correlate with increased cargo transcytosis. Furthermore, we show that the transferrin receptor-targeted immunoliposomes accumulate along the microvessels of the brains of rats, but find no evidence for transcytosis of the immunoliposome. Conversely, the increased accumulation correlated both with increased...

  15. Targeting neurotransmitter receptors with nanoparticles in vivo allows single-molecule tracking in acute brain slices

    Science.gov (United States)

    Varela, Juan A.; Dupuis, Julien P.; Etchepare, Laetitia; Espana, Agnès; Cognet, Laurent; Groc, Laurent

    2016-03-01

    Single-molecule imaging has changed the way we understand many biological mechanisms, particularly in neurobiology, by shedding light on intricate molecular events down to the nanoscale. However, current single-molecule studies in neuroscience have been limited to cultured neurons or organotypic slices, leaving as an open question the existence of fast receptor diffusion in intact brain tissue. Here, for the first time, we targeted dopamine receptors in vivo with functionalized quantum dots and were able to perform single-molecule tracking in acute rat brain slices. We propose a novel delocalized and non-inflammatory way of delivering nanoparticles (NPs) in vivo to the brain, which allowed us to label and track genetically engineered surface dopamine receptors in neocortical neurons, revealing inherent behaviour and receptor activity regulations. We thus propose a NP-based platform for single-molecule studies in the living brain, opening new avenues of research in physiological and pathological animal models.

  16. Characterization and visualization of cholecystokinin receptors in rat brain using [3H]pentagastrin

    International Nuclear Information System (INIS)

    Gaudreau, P.; Quirion, R.; St Pierre, S.; Pert, C.B.

    1983-01-01

    [ 3 H]Pentagastrin binds specifically to an apparent single class of CCK receptors on slide-mounted sections of rat brain (KD . 5.6 nM; Bmax . 36.6 fmol/mg protein). This specific binding is temperature-dependent and regulated by ions and nucleotides. The relative potencies of C-terminal fragments of CCK-8(SO 3 H), benzotript and proglumide in inhibiting specific [ 3 H]pentagastrin binding to CCK brain receptors reinforce the concept of different brain and pancreas CCK receptors. CCK receptors were visualized by using tritium-sensitive LKB film analyzed by computerized densitometry. CCK receptors are highly concentrated in the cortex, dentate gyrus, granular and external plexiform layers of the olfactory bulb, anterior olfactory nuclei, olfactory tubercle, claustrum, accumbens nucleus, some nuclei of the amygdala, thalamus and hypothalamus

  17. Adenosine A1 receptors contribute to immune regulation after neonatal hypoxic ischemic brain injury

    OpenAIRE

    Winerdal, Max; Winerdal, Malin E.; Wang, Ying-Qing; Fredholm, Bertil B.; Winqvist, Ola; Ådén, Ulrika

    2015-01-01

    Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A1 receptor deficiency (A1R−/−) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction siz...

  18. The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined

    DEFF Research Database (Denmark)

    Pinborg, Lars H; Arfan, Haroon; Haugbol, Steven

    2007-01-01

    With the appropriate radiolabeled tracers, positron emission tomography (PET) enables in vivo human brain imaging of markers for neurotransmission, including neurotransmitter synthesis, receptors, and transporters. Whereas structural imaging studies have provided compelling evidence that the human...... brain anatomy is largely genetically determined, it is currently unknown to what degree neuromodulatory markers are subjected to genetic and environmental influence. Changes in serotonin 2A (5-HT(2A)) receptors have been reported to occur in various neuropsychiatric disorders and an association between...

  19. Radioligands for brain 5-HT2 receptor imaging in vivo: why do we need them?

    International Nuclear Information System (INIS)

    Busatto, G.F.

    1996-01-01

    Recently, PET and SPET radiotracers with high specificity for 5-HT 2 receptors have been developed. These have been studied in baboons and humans with promising results, displaying a binding profile compatible with the brain distribution of 5-HT 2 receptors. It is predicted that studies with the newly developed 5-HT radioligands will substantially increase knowledge about the pharmacology of brain disorders. (orig./MG)

  20. [H-3]dihydroalprenolol binding to beta adrenergic receptors in multiple sclerosis brain

    NARCIS (Netherlands)

    Zeinstra, E; Wilczak, N; De Keyser, J

    2000-01-01

    By using immunocytochemistry we previously reported the absence of beta(2) adrenergic receptors on astrocytes in multiple sclerosis (MS) white matter. Here, we measured beta(1) and beta(2) adrenergic receptor concentrations in postmortem brain sections of six MS patients and six controls by using

  1. Temporal and spatial dynamics of corticosteroid receptor down-regulation in rat brain following social defeat

    NARCIS (Netherlands)

    Buwalda, B; Felszeghy, K; Horváth, K M; Nyakas, C; de Boer, S.F.; Bohus, B; Koolhaas, J M

    The experiments explored the nature and time course of changes in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) binding in homogenates of various brain regions and pituitary of male Wistar rats following social defeat stress. One week after defeat, the binding capacity of GRs was

  2. Distribution of kappa opioid receptors in the brain of young and old male rats

    International Nuclear Information System (INIS)

    Maggi, R.; Limonta, P.; Dondi, D.; Martini, L.; Piva, F.

    1989-01-01

    The experiments to be described have been designed in order to: (a) provide new information on the concentrations of opioid kappa receptors in different regions of the brain of the male rats; and (b) to analyze whether the density of brain kappa receptors might be modified by the process of aging. The concentration of kappa receptors was investigated in the hypothalamus, amygdala, mesencephalon, corpus striatum, hippocampus, thalamus, frontal poles, anterior and posterior cortex collected from male rats of 2 and 19 months of age. 3 H-bremazocine (BRZ) was used as the ligand of kappa receptors, after protection of mu and delta receptors respectively with dihydromorphine and d-ala-d-leu-enkephalin. The results obtained show that: (1) in young male rats, the number of kappa opioid receptors is different in the various brain areas examined. (2) Aging exerts little influence on the number of kappa receptors in the majority of the brain structures considered. However in the amygdala and in the thalamus the number of kappa receptors was increased in old animals

  3. Distinct angiotensin II receptor in primary cultures of glial cells from rat brain

    International Nuclear Information System (INIS)

    Raizada, M.K.; Phillips, M.I.; Crews, F.T.; Sumners, C.

    1987-01-01

    Angiotensin II (Ang-II) has profound effects on the brain. Receptors for Ang-II have been demonstrated on neurons, but no relationship between glial cells and Agn-II has been established. Glial cells (from the hypothalamus and brain stem of 1-day-old rat brains) in primary culture have been used to demonstrate the presence of specific Ang-II receptors. Binding of 125 I-Ang-II to glial cultures was rapid, reversible, saturable, and specific for Ang-II. The rank order of potency of 125 I-Ang-II binding was determined. Scatchard analysis revealed a homogeneous population of high-affinity binding sites with a B/sub max/ of 110 fmol/mg of protein. Light-microscopic autoradiography of 125 I-Ang-II binding supported the kinetic data, documenting specific Ang-II receptors on the glial cells. Ang-II stimulated a dose-dependent hydrolysis of phosphatidylinositols in glial cells, an effect mediated by Ang-II receptors. However, Ang-II failed to influence [ 3 H] norepinephrine uptake, and catecholamines failed to regulate Ang-II receptors, effects that occur in neurons. These observations demonstrate the presence of specific Ang-II receptors on the glial cells in primary cultures derived from normotensive rat brain. The receptors are kinetically similar to, but functionally distinct from, the neuronal Ang-II receptors

  4. Transferrin receptor-1 and ferritin heavy and light chains in astrocytic brain tumors

    DEFF Research Database (Denmark)

    Rosager, Ann Mari; Sørensen, Mia D; Dahlrot, Rikke H

    2017-01-01

    Astrocytic brain tumors are the most frequent primary brain tumors. Treatment with radio- and chemotherapy has increased survival making prognostic biomarkers increasingly important. The aim of the present study was to investigate the expression and prognostic value of transferrin receptor-1 (TfR...

  5. Differences in postmortem stability of sex steroid receptor immunoreactivity in rat brain

    NARCIS (Netherlands)

    Fodor, Mariann; van Leeuwen, Fred W.; Swaab, Dick F.

    2002-01-01

    Difficulties in demonstrating sex steroid receptors in the human brain by immunohistochemistry (IHC) may depend on postmortem delay and a long fixation time. The effect of different postmortem times was therefore studied in rat brain kept in the skull at room temperature for 0, 6, or 24 hr after

  6. Nuclear Receptor TLX Regulates Cell Cycle Progression in Neural Stem Cells of the Developing Brain

    OpenAIRE

    Li, Wenwu; Sun, Guoqiang; Yang, Su; Qu, Qiuhao; Nakashima, Kinichi; Shi, Yanhong

    2007-01-01

    TLX is an orphan nuclear receptor that is expressed exclusively in vertebrate forebrains. Although TLX is known to be expressed in embryonic brains, the mechanism by which it influences neural development remains largely unknown. We show here that TLX is expressed specifically in periventricular neural stem cells in embryonic brains. Significant thinning of neocortex was observed in embryonic d 14.5 TLX-null brains with reduced nestin labeling and decreased cell proliferation in the germinal ...

  7. 123I-iomazenil brain receptor SPECT in focal epilepsy. In comparison with 99mTc-HMPAO brain SPECT, MRI and Video/EEG monitoring

    International Nuclear Information System (INIS)

    Xu Hao; Wang Tongge; Huang Li; Michael Cordes

    1998-01-01

    Purpose: To evaluate the clinical value of 123 I-Iomazenil brain receptor SPECT in diagnosis of focal epilepsy in comparison with 99m Tc-HMPAO brain SPECT, MRI and Video/EEG monitoring. Methods 123 I-Iomazenil brain receptor SPECT was performed on 40 patients with focal epilepsy. The results were compared with those obtained by 99m Tc-HMPAO brain SPECT, MRI and Video/EEG monitoring. Results: In 40 patients, the sensitivity of Video/EEG monitoring for localization of epileptogenic area was 95% (38/40). The sensitivity of 123 I-iomazenil brain receptor SPECT, 99m Tc-HMPAO brain SPECT and MRI for localization of epileptogenic area compared with Video/EEG monitoring ('gold standard') was 65.8%(25/38), 55.3%(21/38) and 47.4%(18/38), respectively. The localization of epileptogenic area with 123 I-Iomazenil brain receptor SPECT was in concordance with Video/EEG monitoring in 20 patients, 99m Tc-HMPAO brain SPECT in 15 patients and MRI in 16 patients, respectively. The sensitivity of 123 I-Iomazenil brain receptor SPECT combined with MRI for localization of epileptogenic area was 84.2%(32/38). Conclusions: 123 I-Iomazenil brain receptor SPECT is a useful method in detecting and localizing epileptogenic area. The combination of 123 I-Iomazenil brain receptor SPECT and MRI has a high sensitivity for detecting epileptogenic area

  8. Quantitative autoradiography of ligands for dopamine receptors and transporters in brain of Göttingen minipig

    DEFF Research Database (Denmark)

    Minuzzi, Luciano; Olsen, Aage Kristian; Bender, Dirk

    2006-01-01

    The pig has been used as animal model for positron emission tomography (PET) studies of dopamine (DA) receptors and pharmacological perturbations of DA neurotransmission. However, the binding properties of DA receptors and transporters in pig brain have not been characterized in vitro. Therefore...... in young and old pigs, and were close to those reported for rat and human brain. Furthermore, gradients in the concentrations of D1 and D2/3 sites in striatum measured in vitro agreed with earlier findings in PET studies. However, the dopamine transporter (DAT) ligand [3H]GBR12935 did not bind in pig brain...

  9. Evidence for thymopoietin and thymopoietin/α-bungarotoxin/nicotinic receptors within the brain

    International Nuclear Information System (INIS)

    Quik, M.; Babu, U.; Audhya, T.; Goldstein, G.

    1991-01-01

    Thymopoietin, a polypeptide hormone of the thymus that has pleiotropic actions on the immune, endocrine, and nervous systems, potently interacts with the neuromuscular nicotinic acetylcholine receptor. Thymopoietin binds to the nicotinic α-bungarotoxin (α-BGT) receptor in muscle and, like αBGT, inhibits cholinergic transmission at this site. Evidence is given that radiolabeled thymopoietin similarly binds to a nicotinic α-BGT-binding site within the brain and does so with the characteristics of a specific receptor ligand. Thus specific binding to neuronal membranes was saturable, of high affinity linear with increased tissue concentration, and readily reversible; half-time was ∼5 min for association and 10 min for dissociation. Binding of 125 I-labeled thymopoietin was displaced not only by unlabeled thymopoietin but also by α-BGT and the nicotinic receptor ligands d-tubocurarine and nicotine; various other receptor ligands (muscarinic, adrenergic, and dopaminergic) did not affect binding of 125 I-labeled thymopoietin. Thymopoietin was shown by ELISA to be present in brain extracts, displacement curves of thymus and brain extracts being parallel to the standard thymopoietin curve, and Western (immuno) blot identified in brain and thymus extracts a thymopoietin-immunoreactive polypeptide of the same molecular mass as purified thymopoietin polypeptide. The authors conclude that thymopoietin and thymopoietin-binding sites are present within the brain and that the receptor for thymopoietin is the previously identified nicotinic α-BGT-binding site of neuronal tissue

  10. A method for acetylcholinesterase staining of brain sections previously processed for receptor autoradiography.

    Science.gov (United States)

    Lim, M M; Hammock, E A D; Young, L J

    2004-02-01

    Receptor autoradiography using selective radiolabeled ligands allows visualization of brain receptor distribution and density on film. The resolution of specific brain regions on the film often can be difficult to discern owing to the general spread of the radioactive label and the lack of neuroanatomical landmarks on film. Receptor binding is a chemically harsh protocol that can render the tissue virtually unstainable by Nissl and other conventional stains used to delineate neuroanatomical boundaries of brain regions. We describe a method for acetylcholinesterase (AChE) staining of slides previously processed for receptor binding. AChE staining is a useful tool for delineating major brain nuclei and tracts. AChE staining on sections that have been processed for receptor autoradiography provides a direct comparison of brain regions for more precise neuroanatomical description. We report a detailed thiocholine protocol that is a modification of the Koelle-Friedenwald method to amplify the AChE signal in brain sections previously processed for autoradiography. We also describe several temporal and experimental factors that can affect the density and clarity of the AChE signal when using this protocol.

  11. Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

    Science.gov (United States)

    Glushakov, Alexander V.; Fazal, Jawad A.; Narumiya, Shuh; Doré, Sylvain

    2014-01-01

    Brain injuries promote upregulation of so-called proinflammatory prostaglandins, notably prostaglandin E2 (PGE2), leading to overactivation of a class of its cognate G-protein-coupled receptors, including EP1, which is considered a promising target for treatment of ischemic stroke. However, the role of the EP1 receptor is complex and depends on the type of brain injury. This study is focused on the investigation of the role of the EP1 receptor in a controlled cortical impact (CCI) model, a preclinical model of traumatic brain injury (TBI). The therapeutic effects of post-treatments with a widely studied EP1 receptor antagonist, SC-51089, were examined in wildtype and EP1 receptor knockout C57BL/6 mice. Neurological deficit scores (NDS) were assessed 24 and 48 h following CCI or sham surgery, and brain immunohistochemical pathology was assessed 48 h after surgery. In wildtype mice, CCI resulted in an obvious cortical lesion and localized hippocampal edema with an associated significant increase in NDS compared to sham-operated animals. Post-treatments with the selective EP1 receptor antagonist SC-51089 or genetic knockout of EP1 receptor had no significant effects on cortical lesions and hippocampal swelling or on the NDS 24 and 48 h after CCI. Immunohistochemistry studies revealed CCI-induced gliosis and microglial activation in selected ipsilateral brain regions that were not affected by SC-51089 or in the EP1 receptor-deleted mice. This study provides further clarification on the respective contribution of the EP1 receptor in TBI and suggests that, under this experimental paradigm, the EP1 receptor would have limited effects in modulating acute neurological and anatomical pathologies following contusive brain trauma. Findings from this protocol, in combination with previous studies demonstrating differential roles of EP1 receptor in ischemic, neurotoxic, and hemorrhagic conditions, provide scientific background and further clarification of potential therapeutic

  12. Low 5-HT1B receptor binding in the migraine brain

    DEFF Research Database (Denmark)

    Deen, Marie; Hansen, Hanne D; Hougaard, Anders

    2018-01-01

    Background The pathophysiology of migraine may involve dysfunction of serotonergic signaling. In particular, the 5-HT1B receptor is considered a key player due to the efficacy of 5-HT1B receptor agonists for treatment of migraine attacks. Aim To examine the cerebral 5-HT1B receptor binding....... Patients who reported migraine brain regions involved in pain modulation as regions of interest and applied a latent variable model (LVM) to assess the group effect on binding across these regions. Results Our data...... support a model wherein group status predicts the latent variable ( p = 0.038), with migraine patients having lower 5-HT1B receptor binding across regions compared to controls. Further, in a whole-brain voxel-based analysis, time since last migraine attack correlated positively with 5-HT1B receptor...

  13. Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma

    DEFF Research Database (Denmark)

    Johnsen, Kasper B.; Burkhart, Annette; Melander, Fredrik

    2017-01-01

    Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing...... the possibility of delivering neuroactive drugs by way of receptors already present on the brain endothelium has been of interest for many years. The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we...... investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor-targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does...

  14. The development of the glucocorticoid receptor system in the rat limbic brain. 2

    International Nuclear Information System (INIS)

    Meaney, M.J.; Sapolsky, R.M.; McEwen, B.S.

    1985-01-01

    The authors report the results of an autoradiographic analysis of the postnatal development of the hippocampal glucocorticoid receptor system in the rat brain. Quantitative analysis of the autoradiograms revealed a varied pattern of gradual development towards adult receptor concentrations during the second week of life. Receptor concentrations in the dentate gyrus increased dramatically between Days 9 and 15, while the changes during this period in the pyramidal layers of Ammon's horn seemed to reflect both structural changes in these regions as well as increases in receptor concentrations. (orig.)

  15. Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma.

    Science.gov (United States)

    Johnsen, Kasper Bendix; Burkhart, Annette; Melander, Fredrik; Kempen, Paul Joseph; Vejlebo, Jonas Bruun; Siupka, Piotr; Nielsen, Morten Schallburg; Andresen, Thomas Lars; Moos, Torben

    2017-09-04

    Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibility of delivering neuroactive drugs by way of receptors already present on the brain endothelium has been of interest for many years. The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor-targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does not correlate with increased cargo transcytosis. Furthermore, we show that the transferrin receptor-targeted immunoliposomes accumulate along the microvessels of the brains of rats, but find no evidence for transcytosis of the immunoliposome. Conversely, the increased accumulation correlated both with increased cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain.

  16. Pharmacological and biochemical properties of the benzodiazepine-GABA receptor in codfish brain in comparison with mammalian brain

    International Nuclear Information System (INIS)

    Deng, L.

    1989-01-01

    The GABA receptor of codfish brain is encoded by an ancestral gene of the mammalian GABA receptor based on phylogenetic studies. The mammalian GABA receptor consists of at least two subunits (β and α) which could be photoaffinity labeled by the GABA agonist [ 3 H]muscimol (57 kDa) and the benzodiazepine (BZ) agonist [ 3 H]flunitrazepam (52 kDa), respectively. In contrast, electrophoresis of codfish GABA receptor photoaffinity labeled by the same ligands showed a single radioactive peak on sodium dodecyl surface polyarcylamide gel, giving rise to a relative molecular weight of 56-57 kDa equivalent to the β subunit of 57 kDa in mammals. The homogeneity of purified receptor using benzodiazepine (Ro 7-1986/1) affinity chromatography was further verified by two-dimensional gel electrophoresis based on isoelectric point and molecular weight, in addition to a single band on a silver stained gel and specific activity. The receptor density and affinity constant for [ 3 H]muscimol and [ 3 H]flunitrazepam are comparable to those in bovine, rate, and human brain

  17. Intravenous siRNA of brain cancer with receptor targeting and avidin-biotin technology.

    Science.gov (United States)

    Xia, Chun-Fang; Zhang, Yufeng; Zhang, Yun; Boado, Ruben J; Pardridge, William M

    2007-12-01

    The effective delivery of short interfering RNA (siRNA) to brain following intravenous administration requires the development of a delivery system for transport of the siRNA across the brain capillary endothelial wall, which forms the blood-brain barrier in vivo. siRNA was delivered to brain in vivo with the combined use of a receptor-specific monoclonal antibody delivery system, and avidin-biotin technology. The siRNA was mono-biotinylated on either terminus of the sense strand, in parallel with the production of a conjugate of the targeting MAb and streptavidin. Rat glial cells (C6 or RG-2) were permanently transfected with the luciferase gene, and implanted in the brain of adult rats. Following the formation of intra-cranial tumors, the rats were treated with a single intravenous injection of 270 microg/kg of biotinylated siRNA attached to a transferrin receptor antibody via a biotin-streptavidin linker. The intravenous administration of the siRNA caused a 69-81% decrease in luciferase gene expression in the intracranial brain cancer in vivo. Brain delivery of siRNA following intravenous administration is possible with siRNAs that are targeted to brain with the combined use of receptor specific antibody delivery systems and avidin-biotin technology.

  18. Repeated stressful experiences differently affect brain dopamine receptor subtypes

    International Nuclear Information System (INIS)

    Puglisi-Allegra, S.; Cabib, S.; Kempf, E.; Schleef, C.

    1991-01-01

    The binding of tritiated spiperone (D2 antagonist) and tritiated SCH 23390 (D1 antagonist), in vivo, was investigated in the caudatus putamen (CP) and nucleus accumbens septi (NAS) of mice submitted to ten daily restraint stress sessions. Mice sacrificed 24 hr after the last stressful experience presented a 64% decrease of D2 receptor density (Bmax) but no changes in D1 receptor density in the NAS. In the CP a much smaller (11%) reduction of D2 receptor density was accompanied by a 10% increase of D1 receptors. These results show that the two types of dopamine (DA) receptors adapt in different or even opposite ways to environmental pressure, leading to imbalance between them

  19. Bidirectional apical-basal traffic of the cation-independent mannose-6-phosphate receptor in brain endothelial cells

    DEFF Research Database (Denmark)

    Siupka, Piotr; Hersom, Maria N. S.; Lykke-Hartmann, Karin

    2017-01-01

    Brain capillary endothelium mediates the exchange of nutrients between blood and brain parenchyma. This barrier function of the brain capillaries also limits passage of pharmaceuticals from blood to brain, which hinders treatment of several neurological disorders. Receptor-mediated transport has ...

  20. Cloning and expression of a rat brain α2B-adrenergic receptor

    International Nuclear Information System (INIS)

    Flordellis, C.S.; Handy, D.E.; Bresnahan, M.R.; Zannis, V.I.; Gavras, H.

    1991-01-01

    The authors isolated a cDNA clone (RBα 2B ) and its homologous gene (GRα 2B ) encoding an α 2B -adrenergic receptor subtype by screening a rat brain cDNA and a rat genomic library. Nucleotide sequence analysis showed that both clones code for a protein of 458 amino acids, which is 87% homologous to the human kidney glycosylated adrenergic receptor (α 2 -C4) and divergent from the rat kidney nonglycosylated α 2B subtype (RNGα 2 ). Transient expression of RBα 2B in COS-7 cells resulted in high-affinity saturable binding for [ 3 H]rauwolscine and a high receptor number in the membranes of transfected COS-7 cells. Pharmacological analysis demonstrated that the expressed receptor bound adrenergic ligands with the following order of potency: rauwolscine > yohimbine > prazosin > oxymetazoline, with a prazosin-to-oxymetazoline K i ratio of 0.34. This profile is characteristic of the α 2B -adrenergic receptor subtype. Blotting analysis of rat brain mRNA gave one major and two minor mRNA species, and hybridization with strand-specific probes showed that both DNA strands of GRα 2B may be transcriptionally active. These findings show that rat brain expresses an α 2B -adrenergic receptor subtype that is structurally different from the rat kidney nonglycosylated α 2B subtype. Thus the rat expresses at least two divergent α 2B -adrenergic receptors

  1. A fundamental study on brain receptor mapping by neuronuclear medicine imaging

    International Nuclear Information System (INIS)

    Tsuji, Shiro

    1988-01-01

    The usefulness of autoradiography in the quantitation of the rat brain receptor was evaluated. H-3 spiperone, H-3 quinuclidinyl benzylate (QNB), H-3 muscimol, H-3 diprenorphine, H-3 ketanserin, and H-3 dihydroalprenolol hydrochloride were used for autoradiography. Satisfactory autoradiograms with these H-3 labeled ligants were obtained for incubation time, washing time, and binding curve. The video digitizer system was the most suitable in autoradiography. Using appropriate conditions for the ligand-receptor interaction, receptor autoradiography and in vitro receptor assay were concordant as for the the number of maximum binding sites (Bmax) of the muscarinic acetylcholine receptor and equilibrium dissociation constant (Kd) of its antagonist, H-3 QNB. Receptor autoradiography with high spatial resolution allowed the comparison of Bmax and Kd in the brain. To improve conventional Scatchard analysis, used in the estimation of Bmax and Kd, a new mathematical method was developed for estimating individual rate constants and Bmax on the basis of time courses of association and dissociation. Using the new mathematical method, apparent equilibrium dissociation rate constant was in good agreement with that from a non-isomerization model. Autoradiography may provide a clue for the basic data on brain receptor mapping by a promising emission computerized tomography in neuropsychiatric diseases. (Namekawa, K.)

  2. Distribution of the octopamine receptor AmOA1 in the honey bee brain.

    Directory of Open Access Journals (Sweden)

    Irina Sinakevitch

    2011-01-01

    Full Text Available Octopamine plays an important role in many behaviors in invertebrates. It acts via binding to G protein coupled receptors located on the plasma membrane of responsive cells. Several distinct subtypes of octopamine receptors have been found in invertebrates, yet little is known about the expression pattern of these different receptor subtypes and how each subtype may contribute to different behaviors. One honey bee (Apis mellifera octopamine receptor, AmOA1, was recently cloned and characterized. Here we continue to characterize the AmOA1 receptor by investigating its distribution in the honey bee brain. We used two independent antibodies produced against two distinct peptides in the carboxyl-terminus to study the distribution of the AmOA1 receptor in the honey bee brain. We found that both anti-AmOA1 antibodies revealed labeling of cell body clusters throughout the brain and within the following brain neuropils: the antennal lobes; the calyces, pedunculus, vertical (alpha, gamma and medial (beta lobes of the mushroom body; the optic lobes; the subesophageal ganglion; and the central complex. Double immunofluorescence staining using anti-GABA and anti-AmOA1 receptor antibodies revealed that a population of inhibitory GABAergic local interneurons in the antennal lobes express the AmOA1 receptor in the cell bodies, axons and their endings in the glomeruli. In the mushroom bodies, AmOA1 receptors are expressed in a subpopulation of inhibitory GABAergic feedback neurons that ends in the visual (outer half of basal ring and collar regions and olfactory (lip and inner basal ring region calyx neuropils, as well as in the collar and lip zones of the vertical and medial lobes. The data suggest that one effect of octopamine via AmOA1 in the antennal lobe and mushroom body is to modulate inhibitory neurons.

  3. Effects of alkylating agents on dopamine D(3) receptors in rat brain: selective protection by dopamine.

    Science.gov (United States)

    Zhang, K; Weiss, N T; Tarazi, F I; Kula, N S; Baldessarini, R J

    1999-11-13

    Dopamine D(3) receptors are structurally highly homologous to other D(2)-like dopamine receptors, but differ from them pharmacologically. D(3) receptors are notably resistant to alkylation by 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which readily alkylates D(2) receptors. We compared EEDQ with N-(p-isothiocyanatophenethyl)spiperone (NIPS), a selective D(2)-like receptor alkylating agent, for effects on D(3) and D(2) receptors in rat brain using autoradiographic analysis. Neither agent occluded D(3) receptors in vivo at doses that produced substantial blockade of D(2) receptors, even after catecholamine-depleting pretreatments. In vitro, however, D(3) receptors were readily alkylated by both NIPS (IC(50)=40 nM) and EEDQ (IC(50)=12 microM). These effects on D(3) sites were blocked by nM concentrations of dopamine, whereas microM concentrations were required to protect D(2) receptors from the alkylating agents. The findings are consistent with the view that alkylation of D(3) receptors in vivo is prevented by its high affinity for even minor concentrations of endogenous dopamine.

  4. IRS-1: essential for insulin- and IL-4-stimulated mitogenesis in hematopoietic cells.

    Science.gov (United States)

    Wang, L M; Myers, M G; Sun, X J; Aaronson, S A; White, M; Pierce, J H

    1993-09-17

    Although several interleukin-3 (IL-3)-dependent cell lines proliferate in response to IL-4 or insulin, the 32D line does not. Insulin and IL-4 sensitivity was restored to 32D cells by expression of IRS-1, the principal substrate of the insulin receptor. Although 32D cells possessed receptors for both factors, they lacked the IRS-1--related protein, 4PS, which becomes phosphorylated by tyrosine in insulin- or IL-4--responsive lines after stimulation. These results indicate that factors that bind unrelated receptors can use similar mitogenic signaling pathways in hematopoietic cells and that 4PS and IRS-1 are functionally similar proteins that are essential for insulin- and IL-4--induced proliferation.

  5. Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Gillings, Nic; Madsen, Karine

    2010-01-01

    Pharmacological stimulation of the serotonin 4 (5-HT(4)) receptor has shown promise for treatment of Alzheimer's disease and major depression. A new selective radioligand, [(11)C]SB207145, for positron emission tomography (PET) was used to quantify brain 5-HT(4) receptors in sixteen healthy......(max) was in accordance with post-mortem brain studies (Spearman's r=0.83, p=0.04), and the regional binding potentials, BP(ND), were on average 2.6 in striatum, 0.42 in prefrontal cortex, and 0.91 in hippocampus. We found no effect of sex but a decreased binding with age (p=0.046). A power analysis showed that, given......-HT(4) receptor binding in human brain can be reliably assessed with [(11)C]SB207145, which is encouraging for future PET studies of drug occupancy or patients with neuropsychiatric disorders....

  6. Serotonin 2A receptor agonist binding in the human brain with [C]Cimbi-36

    DEFF Research Database (Denmark)

    Ettrup, A.; da Cunha-Bang, S.; McMahon, Barry P.

    2014-01-01

    [C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely ....... Thus, we here describe [C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT receptors in the human brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 30 April 2014; doi:10.1038/jcbfm.2014.68....... than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT receptors with [C]Cimbi-36 PET. The two-tissue compartment model using arterial input...

  7. In vivo regulation of the serotonin-2 receptor in rat brain

    International Nuclear Information System (INIS)

    Stockmeier, C.A.; Kellar, K.J.

    1986-01-01

    Serotonin-2 (5-HT-2) receptors in brain were measured using ( 3 H)ketanserin. The authors examined the effects of amitriptyline, an anti-depressant drug, of electroconvulsive shock (ECS) and of drug-induced alterations in presynaptic 5-HT function on ( 3 H)ketanserin binding to 5-HT-2 receptors in rat brain. The importance of intact 5-HT axons to the up-regulation of 5-HT-2 receptors by ECS was also investigated, and an attempt was made to relate the ECS-induced increase in this receptor to changes in 5-HT presynaptic mechanisms. Twelve days of ECS increased the number of 5-HT-2 receptors in frontal cortex. Neither the IC 50 nor the Hill coefficient of 5-HT in competing for ( 3 H)ketanserin binding sites was altered by ECS. Repeated injections of amitriptyline reduced the number of 5-HT-2 receptors in frontal cortex. Reserpine, administered daily for 12 days, caused a significant increase in 5-HT-2 receptors, but neither daily injections of p-chlorophenylalanine (PCPA) nor lesions of 5-HT axons with 5,7-dihydroxytryptamine (5,7-DHT) affected 5-HT-2 receptors. However, regulation of 5-HT-2 receptors by ECS was dependent on intact 5-HT axons since ECS could not increase the number of 5-HT-2 receptors in rats previously lesioned with 5,7-DHT. Repeated ECS, however, does not appear to affect either the high-affinity uptake of ( 3 H)5-HT or ( 3 H)imipramine binding, two presynaptic markers of 5-HT neuronal function. 5-HT-2 receptors appear to be under complex control. ECS or drug treatments such as reserpine or amitriptyline, which affect several monoamine neurotransmission systems including 5-HT, can alter 5-HT-2 receptors. 28 references, 1 figure, 7 tables

  8. Insulin-like growth factor-II (IGF II) receptor from rat brain is of lower apparent molecular weight than the IGF II receptor from rat liver

    International Nuclear Information System (INIS)

    McElduff, A.; Poronnik, P.; Baxter, R.C.

    1987-01-01

    The binding subunits of the insulin and insulin-like growth factor-I (IGF I) receptors from rat brain are of lower molecular weight than the corresponding receptor in rat liver, possibly due to variations in sialic acid content. We have compared the IGF II receptor from rat brain and rat liver. The brain receptor is of smaller apparent mol wt (about 10 K) on sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is independent of ligand binding as it persists in iodinated and specifically immunoprecipitated receptors. From studies of wheat germ agglutinin binding and the effect of neuraminidase on receptor mobility, we conclude that this difference is not simply due to variations in sialic acid content. Treatment with endoglycosidase F results in reduction in the molecular size of both liver and brain receptors and after this treatment the aglycoreceptors are of similar size. We conclude that in rat brain tissue the IGF II receptor like the binding subunits of the insulin and IGF I receptors is of lower molecular size than the corresponding receptors in rat liver. This difference is due to differences in N-linked glycosylation

  9. Autoradiographic localization of adenosine receptors in rat brain using [3H]cyclohexyladenosine

    International Nuclear Information System (INIS)

    Goodman, R.R.; Synder, S.H.

    1982-01-01

    Adenosine (A1) receptor binding sites have been localized in rat brain by an in vitro light microscopic autoradiographic method. The binding of [ 3 H]N6-cyclohexyladenosine to slide-mounted rat brain tissue sections has the characteristics of A1 receptors. It is saturable with high affinity and has appropriate pharmacology and stereospecificity. The highest densities of adenosine receptors occur in the molecular layer of the cerebellum, the molecular and polymorphic layers of the hippocampus and dentate gyrus, the medial geniculate body, certain thalamic nuclei, and the lateral septum. High densities also are observed in certain layers of the cerebral cortex, the piriform cortex, the caudate-putamen, the nucleus accumbens, and the granule cell layer of the cerebellum. Most white matter areas, as well as certain gray matter areas, such as the hypothalamus, have negligible receptor concentrations. These localizations suggest possible central nervous system sites of action of adenosine

  10. Volume transmission and receptor-receptor interactions in heteroreceptor complexes: understanding the role of new concepts for brain communication

    Directory of Open Access Journals (Sweden)

    Kjell Fuxe

    2016-01-01

    Full Text Available The discovery of the central monoamine neurons not only demonstrated novel types of brain stem neurons forming global terminal networks all over the brain and the spinal cord, but also to a novel type of communication called volume transmission. It is a major mode of communication in the central nervous system that takes places in the extracellular fluid and the cerebral spinal fluid through diffusion and flow of molecules, like neurotransmitters and extracellular vesicles. The integration of synaptic and volume transmission takes place through allosteric receptor-receptor interactions in heteroreceptor complexes. These heterocomplexes represent major integrator centres in the plasma membrane and their protomers act as moonlighting proteins undergoing dynamic changes and their structure and function. In fact, we propose that the molecular bases of learning and memory can be based on the reorganization of multiples homo and heteroreceptor complexes into novel assembles in the post-junctional membranes of synapses.

  11. A single amino acid substitution is sufficient to modify the mitogenic properties of the epidermal growth factor receptor to resemble that of gp185erbB-2

    DEFF Research Database (Denmark)

    Di Fiore, P P; Helin, K; Kraus, M H

    1992-01-01

    The epidermal growth factor (EGF) receptor (EGFR) and the erbB-2 gene product, gp185erbB-2, exhibit distinct abilities to stimulate mitogenesis in different target cells. By using chimeric molecules between these two receptors, we have previously shown that their intracellular juxtamembrane regio...

  12. Immunologic differentiation of two high-affinity neurotensin receptor isoforms in the developing rat brain.

    Science.gov (United States)

    Boudin, H; Lazaroff, B; Bachelet, C M; Pélaprat, D; Rostène, W; Beaudet, A

    2000-09-11

    Earlier studies have demonstrated overexpression of NT1 neurotensin receptors in rat brain during the first 2 weeks of life. To gain insight into this phenomenon, we investigated the identity and distribution of NT1 receptor proteins in the brain of 10-day-old rats by using two different NT1 antibodies: one (Abi3) directed against the third intracellular loop and the other (Abi4) against the C-terminus of the receptor. Immunoblot experiments that used Abi3 revealed the presence of two differentially glycosylated forms of the NT1 receptor in developing rat brain: one migrating at 54 and the other at 52 kDa. Whereas the 54-kDa form was expressed from birth to adulthood, the 52-kDa form was detected only at 10 and 15 days postnatal. Only the 52-kDa isoform was recognized by Abi4. By immunohistochemistry, both forms of the receptor were found to be predominantly expressed in cerebral cortex and dorsal hippocampus, in keeping with earlier radioligand binding and in situ hybridization data. However, whereas Abi4 immunoreactivity was mainly concentrated within nerve cell bodies and extensively colocalized with the Golgi marker alpha-mannosidase II, Abi3 immunoreactivity was predominantly located along neuronal processes. These results suggest that the transitorily expressed 52-kDa protein corresponds to an immature, incompletely glycosylated and largely intracellular form of the NT1 receptor and that the 54-kDa protein corresponds to a mature, fully glycosylated, and largely membrane-associated form. They also indicate that antibodies directed against different sequences of G-protein-coupled receptors may yield isoform-specific immunohistochemical labeling patterns in mammalian brain. Finally, the selective expression of the short form of the NT1 receptor early in development suggests that it may play a specific role in the establishment of neuronal circuitry. Copyright 2000 Wiley-Liss, Inc.

  13. High abundance androgen receptor in goldfish brain: characteristics and seasonal changes

    International Nuclear Information System (INIS)

    Pasmanik, M.; Callard, G.V.

    1988-01-01

    Testosterone (T) exerts its actions in brain directly via androgen receptors or, after aromatization to estradiol, via estrogen receptors. Brain aromatase activity in teleost fish is 100-1000 times greater than in mammals and would be expected to significantly reduce the quantity of androgen available for receptor binding. Experiments were carried out on the goldfish Carassius auratus to determine if androgen receptors are present in teleost brain and whether their physicochemical properties reflect elevated aromatase. Cytosolic and nuclear extracts were assayed with the use of [ 3 H]T and charcoal, Sephadex LH-20, or DNA-cellulose chromatography to separate bound and free steroids. Binding activity was saturable and had an equally high affinity for T and 5 alpha-dihydrotestosterone. Although mibolerone was a relatively weak competitor, the putative teleost androgen 11-ketotestosterone, methyltrienolone (R1881), estradiol, progesterone, and cortisol were poor ligands. Characteristics that distinguish this receptor from a steroid-binding protein in goldfish serum are the presence of binding activity in both nuclear and cytosolic extracts, a low rate of ligand-receptor dissociation, electrophoretic mobility, sedimentation properties in low vs. high salt, and tissue distribution. DNA cellulose-adhering and nonadhering forms were detected, but these did not differ in other variables measured. Although goldfish androgen receptors resembled those of mammals in all important physicochemical characteristics, they were unusually abundant compared to levels in rat brain, but comparable to levels in prostate and other male sex hormone target organs. Moreover, there were seasonal variations in total receptors, with a peak at spawning (April) 4- to 5-fold higher than values in reproductively inactive fish

  14. Heteromeric α7β2 Nicotinic Acetylcholine Receptors in the Brain

    DEFF Research Database (Denmark)

    Wu, Jie; Liu, Qiang; Tang, Pei

    2016-01-01

    The α7 nicotinic acetylcholine receptor (α7 nAChR) is highly expressed in the brain, where it maintains various neuronal functions including (but not limited to) learning and memory. In addition, the protein expression levels of α7 nAChRs are altered in various brain disorders. The classic rule...... governing α7 nAChR assembly in the mammalian brain was that it was assembled from five α7 subunits to form a homomeric receptor pentamer. However, emerging evidence demonstrates the presence of heteromeric α7 nAChRs in heterologously expressed systems and naturally in brain neurons, where α7 subunits are co...... nAChR, which have provided new insights into the understanding of a novel target of cholinergic signaling....

  15. Human brain receptor autoradiography using whole hemisphere sections: a general method that minimizes tissue artefacts

    International Nuclear Information System (INIS)

    Quirion, R.; Robitaille, Y.; Martial, J.; Chabot, J.G.; Lemoine, P.; Pilapil, C.; Dalpe, M.

    1987-01-01

    A general method for the preparation of high-quality, mostly ice-crystal-artefact-free whole human brain hemisphere sections is described. Upon receipt, hemispheres are divided; one is then fixed in buffered 10% formalin for neuropathological analysis while the other is cut in 8-10-mm-thick coronal slices that are then rapidly frozen in 2-methylbutane at -40 degrees C (10-15 sec) before being placed in the brain bank at -80 degrees C. Such rapid freezing markedly decreases the formation of ice-crystal artefacts. Whole-hemisphere 20-micron thick sections are then cut and mounted onto lantern-type gelatin-coated slides. These sections are subsequently used for both qualitative and quantitative in vitro receptor autoradiography. Examples of data obtained are given by using various radioligands labelling classical neutrotransmitter, neuropeptide, enzyme, and ion channel receptor binding sites. This method should be useful for the obtention of various receptor maps in human brain. Such information could be most useful for in vivo receptor visualization studies using positron emission tomography (PET) scanning. It could also indicate if a given receptor population is specifically and selectively altered in certain brain diseases, eventually leading to the development of new therapeutic approaches

  16. Lactate Receptor Sites Link Neurotransmission, Neurovascular Coupling, and Brain Energy Metabolism

    DEFF Research Database (Denmark)

    Lauritzen, Knut H; Morland, Cecilie; Puchades, Maja

    2013-01-01

    The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiolog......The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated...

  17. Hormonally-mediated Epigenetic Changes to Steroid Receptors in the Developing Brain: Implications for Sexual Differentiation

    Science.gov (United States)

    Nugent, Bridget M.; Schwarz, Jaclyn M.; McCarthy, Margaret M.

    2010-01-01

    The establishment of sex-specific neural morphology, which underlies sex-specific behaviors, occurs during a perinatal sensitive window in which brief exposure to gonadal steroid hormones produces permanent masculinization of the brain. In the rodent, estradiol derived from testicular androgens is a principle organizational hormone. The mechanism by which transient estradiol exposure induces permanent differences in neuronal anatomy has been widely investigated, but remains elusive. Epigenetic changes, such as DNA methylation, allow environmental influences to alter long-term gene expression patterns and therefore may be a potential mediator of estradiol-induced organization of the neonatal brain. Here we review data that demonstrate sex and estradiol-induced differences in DNA methylation on the estrogen receptor α (ERα), estrogen receptor β (ERβ), and progesterone receptor (PR) promoters in sexually dimorphic brain regions across development. Contrary to the overarching view of DNA methylation as a permanent modification directly tied to gene expression, these data demonstrate that methylation patterns on steroid hormone receptors change across the life span and do not necessarily predict expression. Although further exploration into the mechanism and significance of estradiol-induced alterations in DNA methylation patterns in the neonatal brain is necessary, these results provide preliminary evidence that epigenetic alterations can occur in response to early hormone exposure and may mediate estradiol-induced organization of sex differences in the neonatal brain. PMID:20800064

  18. Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Alvarado, M.; Budinger, T.F.; Grossman, R.; Hensley, K.; West, M.S.; Kotake, Y.; Ono, M.; Floyd, R.A.

    2001-12-10

    Following induction of acute neuroinflammation by intracisternal injection of endotoxin (lipopolysaccharide) in rats, quantitative autoradiography was used to assess the regional level of microglial activation and glutamate (NMDA) receptor binding. The possible protective action of the antioxidant phenyl-tert-butyl nitrone in this model was tested by administering the drug in the drinking water for 6 days starting 24 hours after endotoxin injection. Animals were killed 7 days post-injection and consecutive cryostat brain sections labeled with [3H]PK11195 as a marker of activated microglia and [125I]iodoMK801 as a marker of the open-channel, activated state of NMDA receptors. Lipopolysaccharide increased [3H]PK11195 binding in the brain, with the largest increases (2-3 fold) in temporal and entorhinal cortex, hippocampus, and substantia innominata. A significant (>50 percent) decrease in [125I]iodoMK801 binding was found in the same brain regions. Phenyl-tert-butyl nitrone treatment resulted in a partial inhibition ({approx}25 percent decrease) of the lipopolysaccharide-induced increase in [3H]PK11195 binding but completely reversed the lipopolysaccharide-induced decrease in [125I]iodoMK80 binding in the entorhinal cortex, hippocampus, and substantia innominata. Loss of NMDA receptor function in cortical and hippocampal regions may contribute to the cognitive deficits observed in diseases with a neuroinflammatory component, such as meningitis or Alzheimer's disease.

  19. Amtyr1: characterization of a gene from honeybee (Apis mellifera) brain encoding a functional tyramine receptor.

    Science.gov (United States)

    Blenau, W; Balfanz, S; Baumann, A

    2000-03-01

    Biogenic amine receptors are involved in the regulation and modulation of various physiological and behavioral processes in both vertebrates and invertebrates. We have cloned a member of this gene family from the CNS of the honeybee, Apis mellifera. The deduced amino acid sequence is homologous to tyramine receptors cloned from Locusta migratoria and Drosophila melanogaster as well as to an octopamine receptor cloned from Heliothis virescens. Functional properties of the honeybee receptor were studied in stably transfected human embryonic kidney 293 cells. Tyramine reduced forskolin-induced cyclic AMP production in a dose-dependent manner with an EC50 of approximately 130 nM. A similar effect of tyramine was observed in membrane homogenates of honeybee brains. Octopamine also reduced cyclic AMP production in the transfected cell line but was both less potent (EC50 of approximately 3 microM) and less efficacious than tyramine. Receptor-encoding mRNA has a wide-spread distribution in the brain and subesophageal ganglion of the honeybee, suggesting that this tyramine receptor is involved in sensory signal processing as well as in higher-order brain functions.

  20. Identification and characterization of insulin receptors on foetal-mouse brain-cortical cells.

    OpenAIRE

    Van Schravendijk, C F; Hooghe-Peters, E L; De Meyts, P; Pipeleers, D G

    1984-01-01

    The occurrence of insulin receptors was investigated in freshly dissociated brain-cortical cells from mouse embryos. By analogy with classical insulin-binding cell types, binding of 125I-insulin to foetal brain-cortical cells was time- and pH-dependent, only partially reversible, and competed for by unlabelled insulin and closely related peptides. Desalanine-desasparagine-insulin, pig proinsulin, hagfish insulin and turkey insulin were respectively 2%, 4%, 2% and 200% as potent as bovine insu...

  1. In vivo brain dopaminergic receptor site mapping using 75Se-labeled pergolide analogs: the effects of various dopamine receptor agonists and antagonists

    International Nuclear Information System (INIS)

    Weaver, A.

    1986-01-01

    Perogolide mesylate is a new synthetic ergoline derivative which is reported to possess agonistic activity at central dopamine receptor sites in the brain. The authors have synthesized a [ 75 Se]-radiolabeled pergolide mesylate derivative, [ 75 Se]-pergolide tartrate, which, after i.v. administration to mature male rats, showed a time course differentiation in the uptake of this radiolabeled compound in isolated peripheral and central (brain) tissues that are known to be rich in dopamine receptor sites. Further studies were conducted in which the animals were preexposed to the dopamine receptor agonist SKF-38393, as well as the dopamine receptor antagonists (+)-butaclamol, (-)-butaclamol, (+/-)-butaclamol and (-)-chloroethylnorapomorphine, to substantiate the specific peripheral and central localization patterns of [ 75 Se]-pergolide tartrate. Further investigations were also conducted in which the animals received an i.v. administration of N-isopropyl-l-123-p-iodoamphetamine ([ 123 I]-iodoamphetamine). However, [ 123 I]-iodoamphetamine did not demonstrate a specific affinity for any type of receptor site in the brain. These investigations further substantiated the fact that [ 75 Se]-pergolide tartrate does cross the blood-brain barrier is quickly localized at specific dopamine receptor sites in the intact rat brain and that this localization pattern can be affected by preexposure to different dopamine receptor agonists and antagonists. Therefore, these investigations provided further evidence that [ 75 Se]-pergolide tartrate and other radiolabeled ergoline analogs might be useful as brain dopamine receptor localization radiopharmaceuticals

  2. Increased brain dopamine and dopamine receptors in schizophrenia

    International Nuclear Information System (INIS)

    Mackay, A.V.; Iversen, L.L.; Rossor, M.; Spokes, E.; Bird, E.; Arregui, A.; Creese, I.; Synder, S.H.

    1982-01-01

    In postmortem samples of caudate nucleus and nucleus accumbens from 48 schizophrenic patients, there were significant increases in both the maximum number of binding sites (Bmax) and the apparent dissociation constant (KD) for tritiated spiperone. The increase in apparent KD probably reflects the presence of residual neuroleptic drugs, but changes in Bmax for tritiated spiperone reflect genuine changes in receptor numbers. The increases in receptors were seen only in patients in whom neuroleptic medication had been maintained until the time of death, indicating that they may be entirely iatrogenic. Dopamine measurements for a larger series of schizophrenic and control cases (n greater than 60) show significantly increased concentrations in both the nucleus accumbens and caudate nucleus. The changes in dopamine were not obviously related to neuroleptic medication and, unlike the receptor changes, were most severe in younger patients

  3. Channel opening of γ-aminobutyric acid receptor from rat brain: molecular mechanisms of the receptor responses

    International Nuclear Information System (INIS)

    Cash, D.J.; Subbarao, K.

    1987-01-01

    The function of γ-aminobutyric acid (GABA) receptors, which mediate transmembrane chloride flux, can be studied by use of 36 Cl - isotope tracer with membrane from mammalian brain by quench-flow technique, with reaction times that allow resolution of the receptor desensitization rates from the ion flux rates. The rates of chloride exchange into the vesicles in the absence and presence of GABA were characterized with membrane from rat cerebral cortex. Unspecific 36 Cl - influx was completed in three phases of ca. 3% (t/sub 1/2/ = 0.6 s), 56% (t/sub 1/2 = 82 s), and 41% (t/sub 1/2 = 23 min). GABA-mediated, specific chloride exchange occurred with 6.5% of the total vesicular internal volume. The GABA-dependent 36 Cl - influx proceeded in two phases, each progressively slowed by desensitization. The measurements supported the presence of two distinguishable active GABA receptors on the same membrane mediating chloride exchange into the vesicles. The half-response concentrations were similar for both receptors. The two receptors were present in the activity ratio of ca. 4/1, similar to the ratio of low affinity to high-affinity GABA sites found in ligand binding experiments. The desensitization rates have a different dependence on GABA concentration than the channel-opening equilibria. For both receptors, the measurements over a 2000-fold GABA concentration range required a minimal mechanism involving the occupation of both of the two GABA binding sites for significant channel opening; then the receptors were ca. 80% open. Similarly for both receptors, desensitization was mediated by a different pair of binding sites, although desensitization with only one ligand molecule bound could occur at a 20-fold slower rate

  4. Tyrosine phosphorylation of a 66KD soluble protein and augmentation of lectin induced mitogenesis by DMSO in human T lymphocytes

    International Nuclear Information System (INIS)

    Wedner, H.J.; Bass, G.

    1986-01-01

    The authors have demonstrated that induction of mitogenesis in human T lymphocytes is associated with the tyrosine phosphorylation of a 66KD soluble substrate-TPP 66. Since DMSO has been shown to be a non-specific stimulator of tyrosine protein kinases they have examined the effect of DMSO on both activation and tyrosine phosphorylation in human T cells. Human peripheral blood T lymphocytes were isolated by dextran sedimentation, Ficol/Paque centrifugation and nylon wool filtration. Phosphorylation was performed in cells incubated with [ 32 P] orthophosphate followed by DMSO for 30 min. TPP 66 was identified by 2-D PAGE, autoradiography, and HV electrophoresis of the hydrolyzed protein. Concentrations of DMSO from 1% to 50% induced the tyrosine phosphorylation of TPP 66 with maximal stimulation seen at 20%. DMSO alone did not activate the T cells (measured by [ 3 H] thymidine incorporation) when tested at high concentrations for 30 sec to 10 min. (longer incubations were markedly toxic) or low concentrations for 12 to 48 hrs. Low concentrations of DMSO 0.1%-0.5% did however, markedly augment [ 3 H] thymidine incorporation induced by PHA or Con A. These data suggest that tyrosine phosphorylation of TPP 66 alone may not constitute sufficient signal for the activation sequence to begin but the phosphorylation of this soluble substrate may be a critical factor in the propagation of the activation sequence

  5. Impact of Estrogens and Estrogen Receptor Alpha (ESR1) in Brain Lipid Metabolism.

    Science.gov (United States)

    Morselli, Eugenia; de Souza Santos, Roberta; Gao, Su; Ávalos, Yenniffer; Criollo, Alfredo; Palmer, Biff F; Clegg, Deborah J

    2018-03-06

    Estrogens and their receptors play key roles in regulating body weight, energy expenditure, and metabolic homeostasis. It is known that lack of estrogens promotes increased food intake and induces the expansion of adipose tissues, for which much is known. An area of estrogenic research that has received less attention is the role of estrogens and their receptors in influencing intermediary lipid metabolism in organs such as the brain. In this review, we highlight the actions of estrogens and their receptors in regulating their impact on modulating fatty acid content, utilization, and oxidation through their direct impact on intracellular signaling cascades within the central nervous system.

  6. Toll-like receptors in brain development and homeostasis

    DEFF Research Database (Denmark)

    Larsen, Peter H; Holm, Thomas Hellesøe; Owens, Trevor

    2007-01-01

    Toll-like receptors (TLRs) are best known as initiators of the innate immune response to pathogens. Recent reports now reveal intriguing roles for TLRs in the central nervous system (CNS). These include the regulation of neuroinflammation and of neurite outgrowth. The archetypal Toll protein in D...

  7. Protective Angiotensin Type 2 Receptors in the Brain and Hypertension

    DEFF Research Database (Denmark)

    de Kloet, Annette D; Steckelings, Ulrike M; Sumners, Colin

    2017-01-01

    in the brain, particularly within or near cardiovascular control centers, mesh well with findings from pharmacological and gene transfer studies which demonstrate that activation of central AT2R can influence cardiovascular regulation. Collectively, these studies indicate that selective activation of brain AT2......R causes moderate decreases in blood pressure in normal animals and more profound anti-hypertensive effects, along with restoration of baroreflex function, in rodent models of neurogenic hypertension. These findings have opened the door to studies that can (i) assess the role of specific AT2R neuron...

  8. GABA-A Receptors Mediate Tonic Inhibition and Neurosteroid Sensitivity in the Brain.

    Science.gov (United States)

    Reddy, Doodipala Samba

    2018-01-01

    Neurosteroids like allopregnanolone (AP) are positive allosteric modulators of synaptic and extrasynaptic GABA-A receptors. AP and related neurosteroids exhibit a greater potency for δ-containing extrasynaptic receptors. The δGABA-A receptors, which are expressed extrasynaptically in the dentate gyrus and other regions, contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. Levels of endogenous neurosteroids fluctuate with ovarian cycle. Natural and synthetic neurosteroids maximally potentiate tonic inhibition in the hippocampus and provide robust protection against a variety of limbic seizures and status epilepticus. Recently, a consensus neurosteroid pharmacophore model has been proposed at extrasynaptic δGABA-A receptors based on structure-activity relationship for functional activation of tonic currents and seizure protection. Aside from anticonvulsant actions, neurosteroids have been found to be powerful anxiolytic and anesthetic agents. Neurosteroids and Zn 2+ have preferential affinity for δ-containing receptors. Thus, Zn 2+ can prevent neurosteroid activation of extrasynaptic δGABA-A receptor-mediated tonic inhibition. Recently, we demonstrated that Zn 2+ selectively inhibits extrasynaptic δGABA-A receptors and thereby fully prevents AP activation of tonic inhibition and seizure protection. We confirmed that neurosteroids exhibit greater sensitivity at extrasynaptic δGABA-A receptors. Overall, extrasynaptic GABA-A receptors are primary mediators of tonic inhibition in the brain and play a key role in the pathophysiology of epilepsy and other neurological disorders. © 2018 Elsevier Inc. All rights reserved.

  9. Estrogen alters the diurnal rhythm of alpha 1-adrenergic receptor densities in selected brain regions

    Energy Technology Data Exchange (ETDEWEB)

    Weiland, N.G.; Wise, P.M.

    1987-11-01

    Norepinephrine regulates the proestrous and estradiol-induced LH surge by binding to alpha 1-adrenergic receptors. The density of alpha 1-receptors may be regulated by estradiol, photoperiod, and noradrenergic neuronal activity. We wished to determine whether alpha 1-receptors exhibit a diurnal rhythm in ovariectomized and/or estradiol-treated female rats, whether estradiol regulates alpha 1-receptors in those areas of brain involved with LH secretion and/or sexual behavior, and whether the concentrations of alpha-receptors vary inversely relative to previously reported norepinephrine turnover patterns. Young female rats, maintained on a 14:10 light-dark cycle were ovariectomized. One week later, half of them were outfitted sc with Silastic capsules containing estradiol. Groups of animals were decapitated 2 days later at 0300, 1000, 1300, 1500, 1800, and 2300 h. Brains were removed, frozen, and sectioned at 20 micron. Sections were incubated with (/sup 3/H)prazosin in Tris-HCl buffer, washed, dried, and exposed to LKB Ultrofilm. The densities of alpha 1-receptors were quantitated using a computerized image analysis system. In ovariectomized rats, the density of alpha 1-receptors exhibited a diurnal rhythm in the suprachiasmatic nucleus (SCN), medial preoptic nucleus (MPN), and pineal gland. In SCN and MPN, receptor concentrations were lowest during the middle of the day and rose to peak levels at 1800 h. In the pineal gland, the density of alpha 1-receptors was lowest at middark phase, rose to peak levels before lights on, and remained elevated during the day. Estradiol suppressed the density of alpha 1 binding sites in the SCN, MPN, median eminence, ventromedial nucleus, and the pineal gland but had no effect on the lateral septum. Estrogen treatment altered the rhythm of receptor densities in MPN, median eminence, and the pineal gland.

  10. Estrogen alters the diurnal rhythm of alpha 1-adrenergic receptor densities in selected brain regions

    International Nuclear Information System (INIS)

    Weiland, N.G.; Wise, P.M.

    1987-01-01

    Norepinephrine regulates the proestrous and estradiol-induced LH surge by binding to alpha 1-adrenergic receptors. The density of alpha 1-receptors may be regulated by estradiol, photoperiod, and noradrenergic neuronal activity. We wished to determine whether alpha 1-receptors exhibit a diurnal rhythm in ovariectomized and/or estradiol-treated female rats, whether estradiol regulates alpha 1-receptors in those areas of brain involved with LH secretion and/or sexual behavior, and whether the concentrations of alpha-receptors vary inversely relative to previously reported norepinephrine turnover patterns. Young female rats, maintained on a 14:10 light-dark cycle were ovariectomized. One week later, half of them were outfitted sc with Silastic capsules containing estradiol. Groups of animals were decapitated 2 days later at 0300, 1000, 1300, 1500, 1800, and 2300 h. Brains were removed, frozen, and sectioned at 20 micron. Sections were incubated with [ 3 H]prazosin in Tris-HCl buffer, washed, dried, and exposed to LKB Ultrofilm. The densities of alpha 1-receptors were quantitated using a computerized image analysis system. In ovariectomized rats, the density of alpha 1-receptors exhibited a diurnal rhythm in the suprachiasmatic nucleus (SCN), medial preoptic nucleus (MPN), and pineal gland. In SCN and MPN, receptor concentrations were lowest during the middle of the day and rose to peak levels at 1800 h. In the pineal gland, the density of alpha 1-receptors was lowest at middark phase, rose to peak levels before lights on, and remained elevated during the day. Estradiol suppressed the density of alpha 1 binding sites in the SCN, MPN, median eminence, ventromedial nucleus, and the pineal gland but had no effect on the lateral septum. Estrogen treatment altered the rhythm of receptor densities in MPN, median eminence, and the pineal gland

  11. Brain receptors for thyrotropin releasing hormone in morphine tolerant-dependent rats

    Energy Technology Data Exchange (ETDEWEB)

    Bhargava, H.N.; Das, S.

    1986-03-01

    The effect of chronic treatment of rats with morphine and its subsequent withdrawal on the brain receptors for thyrotropin releasing hormone (TRH) labeled with /sup 3/H-(3MeHis/sup 2/)TRH (MeTRH). Male Sprague Dawley rats were implanted with 4 morphine pellets (each containing 75 mg morphine base) during a 3-day period. Placebo pellet implanted rats served as controls. Both tolerance to and dependence on morphine developed as a result of this procedure. For characterization of brain TRH receptors, the animals were sacrificed 72 h after the implantation of first pellet. In another set of animals the pellets were removed and were sacrificed 24 h later. The binding of /sup 3/H-MeTRH to membranes prepared from brain without the cerebellum was determined. /sup 3/H-MeTRH bound to brain membranes prepared from placebo pellet implanted rats at a single high affinity site with a B/sub max/ value of 33.50 +/- 0.97 fmol/mg protein and a K/sub d/ of 5.18 +/- 0.21 nM. Implantation of morphine pellets did not alter the B/sub max/ value of /sup 3/H-MeTRH but decreased the K/sub d/ value significantly. Abrupt or naloxone precipitated withdrawal of morphine did not alter B/sub max/ or the K/sub d/ values. The binding of /sup 3/H-MeTRH to brain areas was also determined. The results suggest that the development of tolerance to morphine is associated with enhanced sensitivity of brain TRH receptors, however abrupt withdrawal of morphine does not change the characteristics of brain TRH receptors.

  12. Icotinib combined whole brain radiotherapy for patients with brain metastasis from lung adenocarcinoma harboring epidermal growth factor receptor mutation.

    Science.gov (United States)

    Li, Jin-Rui; Zhang, Ye; Zheng, Jia-Lian

    2016-07-01

    The brain is a metastatic organ that is most prone to lung adenocarcinoma (LAC). However, the prognosis of patients with brain metastasis remains very poor. In this study, we evaluated the efficacy of icotinib plus whole brain radiation therapy (WBRT) for treating patients with brain metastasis from epidermal growth factor receptor (EGFR)-mutated LAC. All patients received standard WBRT administered to the whole brain in 30 Gy in 10 daily fractions. Each patient was also instructed to take 125 mg icotinib thrice per day beginning from the first day of the WBRT. After completing the WBRT, maintenance icotinib was administered until the disease progressed or intolerable adverse effects were observed. Cranial progression-free survival (CPFS) and overall survival (OS) times were the primary endpoints. A total of 43 patients were enrolled in this study. Two patients (4.7%) presented a complete response (CR), whereas 20 patients (46.5%) presented a partial response (PR). The median CPFS and OS times were 11.0 and 15.0 months, respectively. The one-year CPFS rate was 40.0% for the patients harboring EGFR exon 19 deletion and 16.7% for the patients with EGFR exon 21 L858R (P=0.027). The concurrent administration of icotinib and WBRT exhibited favorable effects on the patients with brain metastasis. EGFR exon 19 deletion was predictive of a long CPFS following icotinib plus WBRT.

  13. Brain mineralocorticoid receptors as resilience factor under adverse life conditions?

    NARCIS (Netherlands)

    Kanatsou, S.

    2016-01-01

    Studies in human cohorts have underlined the importance of gene-environment interactions for brain structure and function during development and in adulthood. Such interactions can make the difference between staying healthy or succumbing to disease, e.g. depression or posttraumatic stress disorder.

  14. Decreased alternative splicing of estrogen receptor-α mRNA in the Alzheimer's disease brain

    NARCIS (Netherlands)

    Ishunina, Tatjana A.; Swaab, Dick F.

    2012-01-01

    In this study we identified 62 estrogen receptor alpha (ERα) mRNA splice variants in different human brain areas of Alzheimer's disease (AD) and control cases and classified them into 12 groups. Forty-eight of these splice forms were identified for the first time. The distribution of alternatively

  15. Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

    Science.gov (United States)

    In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. The objective of this study is to compare BDNF concentrations of subjects wi...

  16. GLP-1 Receptor Activation Modulates Appetite- and Reward-Related Brain Areas in Humans

    NARCIS (Netherlands)

    van Bloemendaal, L.; IJzerman, R.G.; ten Kulve, J.S.; Barkhof, F.; Konrad, R.J.; Drent, M.L.; Veltman, D.J.; Diamant, M.

    2014-01-01

    Gut-derived hormones, such as GLP-1, have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety, leading to decreases in food intake and body weight. We

  17. Combined autoradiographic-immunocytochemical analysis of opioid receptors and opioid peptide neuronal systems in brain

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, M.E.; Khachaturian, H.; Watson, S.J.

    1985-01-01

    Using adjacent section autoradiography-immunocytochemistry, the distribution of (TH)naloxone binding sites was studied in relation to neuronal systems containing (Leu)enkephalin, dynorphin A, or beta-endorphin immunoreactivity in rat brain. Brain sections from formaldehyde-perfused rats show robust specific binding of (TH)naloxone, the pharmacological (mu-like) properties of which appear unaltered. In contrast, specific binding of the delta ligand (TH)D-Ala2,D-Leu5-enkephalin was virtually totally eliminated as a result of formaldehyde perfusion. Using adjacent section analysis, the authors have noted associations between (TH)naloxone binding sites and one, two, or all three opioid systems in different brain regions; however, in some areas, no apparent relationship could be observed. Within regions, the relationship was complex. The complexity of the association between (TH)naloxone binding sites and the multiple opioid systems, and previous reports of co-localization of mu and kappa receptors in rat brain, are inconsistent with a simple-one-to-one relationship between a given opioid precursor and opioid receptor subtype. Instead, since differential processing of the three precursors gives rise to peptides of varying receptor subtype potencies and selectivities, the multiple peptide-receptor relationships may point to a key role of post-translational processing in determining the physiological consequences of opioid neurotransmission.

  18. Data on overlapping brain disorders and emerging drug targets in human Dopamine Receptors Interaction Network

    Directory of Open Access Journals (Sweden)

    Avijit Podder

    2017-06-01

    Full Text Available Intercommunication of Dopamine Receptors (DRs with their associate protein partners is crucial to maintain regular brain function in human. Majority of the brain disorders arise due to malfunctioning of such communication process. Hence, contributions of genetic factors, as well as phenotypic indications for various neurological and psychiatric disorders are often attributed as sharing in nature. In our earlier research article entitled “Human Dopamine Receptors Interaction Network (DRIN: a systems biology perspective on topology, stability and functionality of the network” (Podder et al., 2014 [1], we had depicted a holistic interaction map of human Dopamine Receptors. Given emphasis on the topological parameters, we had characterized the functionality along with the vulnerable properties of the network. In support of this, we hereby provide an additional data highlighting the genetic overlapping of various brain disorders in the network. The data indicates the sharing nature of disease genes for various neurological and psychiatric disorders in dopamine receptors connecting protein-protein interactions network. The data also indicates toward an alternative approach to prioritize proteins for overlapping brain disorders as valuable drug targets in the network.

  19. [3H]cytisine binding to nicotinic cholinergic receptors in brain

    International Nuclear Information System (INIS)

    Pabreza, L.A.; Dhawan, S.; Kellar, K.J.

    1991-01-01

    Cytisine, a ganglionic agonist, competes with high affinity for brain nicotinic cholinergic receptors labeled by any of several nicotinic 3 H-agonist ligands. Here we have examined the binding of [ 3 H]cytisine in rat brain homogenates. [ 3 H]Cytisine binds with high affinity (Kd less than 1 nM), and specific binding represented 60-90% of total binding at all concentrations examined up to 15 nM. The nicotinic cholinergic agonists nicotine, acetylcholine, and carbachol compete with high affinity for [ 3 H]cytisine binding sites, whereas among nicotinic receptor antagonists only dihydro-beta-erythroidine competes with high affinity (in the nanomolar range). Comparison of binding in several brain regions showed that [ 3 H]cytisine binding is higher in the thalamus, striatum, and cortex than in the hippocampus, cerebellum, or hypothalamus. The pharmacology and brain regional distribution of [ 3 H]cytisine binding sites are those predicted for neuronal nicotinic receptor agonist recognition sites. The high affinity and low nonspecific binding of [ 3 H]cytisine should make it a very useful ligand for studying neuronal nicotinic receptors

  20. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs

    DEFF Research Database (Denmark)

    Eigenmann, Daniela Elisabeth; Dürig, Carmen; Jähne, Evelyn Andrea

    2016-01-01

    The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by c...

  1. Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

    NARCIS (Netherlands)

    Zalachoras, I.; Houtman, R.; Atucha, E.; Devos, R.; Tijssen, A.M.I.; Hu, P.; Lockey, P.M.; Datson, N.A.; Belanoff, J.K.; Lucassen, P.J.; Joëls, M.; de Kloet, E.R.; Roozendaal, B.; Hunt, H.; Meijer, O.C.

    2013-01-01

    Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels.

  2. The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity.

    Science.gov (United States)

    Miner, Jonathan J; Daniels, Brian P; Shrestha, Bimmi; Proenca-Modena, Jose L; Lew, Erin D; Lazear, Helen M; Gorman, Matthew J; Lemke, Greg; Klein, Robyn S; Diamond, Michael S

    2015-12-01

    The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.

  3. Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Gillings, Nic; Comley, Robert A

    2009-01-01

    The serotonin 4 receptor (5-HT(4) receptor) is known to be involved in learning and memory. We evaluated for the first time the quantification of a novel 5-HT(4) receptor radioligand, (11)C-SB207145, for in vivo brain imaging with PET in humans. METHODS: For evaluation of reproducibility, 6...

  4. Desensitization of γ-aminobutyric acid receptor from rat brain: two distinguishable receptors on the same membrane

    International Nuclear Information System (INIS)

    Cash, D.J.; Subbarao, K.

    1987-01-01

    Transmembrane chloride flux mediated by γ-aminobutyric acid (GABA) receptor can be measured with a mammalian brain homogenate preparation containing sealed membrane vesicles. The preparation can be mixed rapidly with solutions of defined composition. Influx of 36 Cl - tracer initiated by mixing with GABA was rapidly terminated by mixing with bicuculline methiodide. The decrease in the isotope influx measurement due to prior incubation of the vesicle preparation with GABA, which increased with preincubation time and GABA concentration, was attributed to desensitization of the GABA receptor. By varying the time of preincubation with GABA between 10 ms and 50 s with quench-flow technique, the desensitization rates could be measured over their whole time course independently of the chloride ion flux rate. Most of the receptor activity decreased in a fast phase of desensitization complete in 200 ms at saturation with GABA. Remaining activity was desensitized in a few seconds. These two phases of desensitization were each kinetically first order and were shown to correspond with two distinguishable GABA receptors on the same membrane. The receptor activities could be estimated, and the faster desensitizing receptor was the predominant one, giving on average ca. 80% of the total activity. The half-response concentrations were similar, 150 and 114 μM for the major and minor receptors, respectively. The dependence on GABA concentration indicated that desensitization is mediated by two GABA binding sites. The fast desensitization rate was approximately 20-fold faster than previously reported rates while the slower desensitization rate was slightly faster than previously reported rates

  5. Evidence that the EphA2 receptor exacerbates ischemic brain injury.

    Directory of Open Access Journals (Sweden)

    John Thundyil

    Full Text Available Ephrin (Eph signaling within the central nervous system is known to modulate axon guidance, synaptic plasticity, and to promote long-term potentiation. We investigated the potential involvement of EphA2 receptors in ischemic stroke-induced brain inflammation in a mouse model of focal stroke. Cerebral ischemia was induced in male C57Bl6/J wild-type (WT and EphA2-deficient (EphA2(-/- mice by middle cerebral artery occlusion (MCAO; 60 min, followed by reperfusion (24 or 72 h. Brain infarction was measured using triphenyltetrazolium chloride staining. Neurological deficit scores and brain infarct volumes were significantly less in EphA2(-/- mice compared with WT controls. This protection by EphA2 deletion was associated with a comparative decrease in brain edema, blood-brain barrier damage, MMP-9 expression and leukocyte infiltration, and higher expression levels of the tight junction protein, zona occludens-1. Moreover, EphA2(-/- brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3 and BAX, and higher levels of the anti-apoptotic protein, Bcl-2 as compared to WT group. We confirmed that isolated WT cortical neurons express the EphA2 receptor and its ligands (ephrin-A1-A3. Furthermore, expression of all four proteins was increased in WT primary cortical neurons following 24 h of glucose deprivation, and in the brains of WT mice following stroke. Glucose deprivation induced less cell death in primary neurons from EphA2(-/- compared with WT mice. In conclusion, our data provide the first evidence that the EphA2 receptor directly contributes to blood-brain barrier damage and neuronal death following ischemic stroke.

  6. Circulating Insulin-Like Growth Factor I Regulates Its Receptor in the Brain of Male Mice.

    Science.gov (United States)

    Trueba-Saiz, A; Fernandez, A M; Nishijima, T; Mecha, M; Santi, A; Munive, V; Aleman, I Torres

    2017-02-01

    The role of IGF-1 and its receptor (IGF-1R) in brain pathology is still unclear. Thus, either reduction of IGF-IR or treatment with IGF-1, two apparently opposite actions, has proven beneficial in brain diseases such as Alzheimer's dementia. A possible explanation of this discrepancy is that IGF-1 down-regulates brain IGF-1R levels, as previously seen in a mouse Alzheimer's dementia model. We now explored whether under normal conditions IGF-1 modulates its receptor. We first observed that in vitro, IGF-1 reduced IGF-1R mRNA levels in all types of brain cells including neurons, astrocytes, microglia, endothelial cells, and oligodendrocytes. IGF-1 also inhibited its own expression in neurons and brain endothelium. Next, we analyzed the in vivo actions of IGF-1. Because serum IGF-1 can enter the brain, we injected mice with IGF-1 ip. As soon as 1 hour after the injection, decreased hippocampal IGF-1 levels were observed, followed by increased IGF-1 and IGF-1R mRNAs 6 hours later. Because environmental enrichment (EE) stimulates the entrance of serum IGF-1 into the brain, we analyzed whether a physiological entrance of IGF-1 also produced changes in brain IGF-1R. Stimulation of IGF-1R by EE triggered a gradual decrease in hippocampal IGF-1 levels. After 6 hours of EE exposure, IGF-1 levels reached a significant decrease in parallel with increased IGF-1R expression. After longer times, IGF-1R mRNA levels returned to baseline. Thus, under nonpathological conditions, IGF-1 regulates brain IGF-1R. Because baseline IGF-1R levels are rapidly restored, a tight control of brain IGF-1R expression seems to operate under physiological conditions. Copyright © 2017 by the Endocrine Society.

  7. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier

    International Nuclear Information System (INIS)

    Friden, P.M.; Walus, L.R.; Musso, G.F.; Taylor, M.A.; Malfroy, B.; Starzyk, R.M.

    1991-01-01

    Delivery of nonlipophilic drugs to the brain is hindered by the tightly apposed capillary endothelial cells that make up the blood-brain barrier. The authors have examined the ability of a monoclonal antibody (OX-26), which recognizes the rat transferrin receptor, to function as a carrier for the delivery of drugs across the blood-brain barrier. This antibody, which was previously shown to bind preferentially to capillary endothelial cells in the brain after intravenous administration, labels the entire cerebrovascular bed in a dose-dependent manner. The initially uniform labeling of brain capillaries becomes extremely punctate ∼ 4 hr after injection, suggesting a time-dependent sequestering of the antibody. Capillary-depletion experiments, in which the brain is separated into capillary and parenchymal fractions, show a time-dependent migration of radiolabeled antibody from the capillaries into the brain parenchyma, which is consistent with the transcytosis of compounds across the blood-brain barrier. Antibody-methotrexate conjugates were tested in vivo to assess the carrier ability of this antibody. Immunohistochemical staining for either component of an OX-26-methotrexate conjugate revealed patterns of cerebrovascular labeling identical to those observed with the unaltered antibody. Accumulation of radiolabeled methotrexate in the brain parenchyma is greatly enhanced when the drug is conjugated to OX-26

  8. Characterization of the gamma-aminobutyric acid receptor system in human brain gliomas

    International Nuclear Information System (INIS)

    Frattola, L.; Ferrarese, C.; Canal, N.; Gaini, S.M.; Galluso, R.; Piolti, R.; Trabucchi, M.

    1985-01-01

    The properties of [ 3 H]-gamma-aminobutyric acid [( 3 H]GABA) binding were studied in biopsied specimens from normal human brain and from 18 cases of human brain gliomas, made up of 6 astrocytomas, 6 glioblastomas, 3 oligodendrogliomas, and 3 medulloblastomas. In fresh membranes obtained from normal gray and white matter one population of Na+-dependent GABA receptors was observed, while in the frozen Triton X-100-treated membranes two distinct populations of Na+-independent binding sites were detected. Specific GABA binding sites in brain gliomas were shown only in frozen Triton X-100-treated membranes. As in normal tissue, these receptors are Na+-independent and bind [ 3 H]GABA with two distinct affinity components. The biochemical profiles of [ 3 H]GABA binding to membranes obtained from different tumors of glial origin are quite similar and cannot be related to the degree of malignancy of the neoplasia

  9. The effect of ZMS on brain M receptor in aged rats

    International Nuclear Information System (INIS)

    Hu Mei; Hu Yaer; Zhang Wei; Xia Zongqin

    2001-01-01

    Objective: The purpose of this work was to study the effect of ZMS, an active component of Yin tonic, Zhimu, on brain M 2 receptor density of aged animals and its correlation with the effect on learning/memory ability. Methods: A dual-site competitive binding assay using 3 H-quinuclidinyl benzilate (QNB) as non selective radioligand and unlabelled Methoctramine as selective competitive agent was established for measuring M 2 receptor density in aged rats. Results: In addition to the change of total density of M receptors, the density of a subtype of M receptors, M 2 receptor in brain was significantly decreased in aged rats [(231.8 +- 115.9) fmol·mg -1 (x-bar +- s) in young rats and (97.9 +- 46.3) fmol·mg -1 in aged rats]. When the aged rats were treated with ZMS for two months, in addition to the up-regulation of total M receptors, the M 2 receptor was up-regulated significantly [being (213 +- 77) mg at a ZMS dose of 3.6 mg·kg -1 ·d - '1, and (212 +- 72) mg at a ZMS dose of 18 mg·kg -1 ·d -1 ]. When the correlation between M 2 or total M receptor densities and the learning/memory ability measured by Y-maze performance was examined with linear regression, the correlation coefficient was remarkable (0.721 and 0.505, respectively). Conclusions: ZMS has the ability of up-regulating M 2 receptor and this may be an important factor for the improvement of learning and memory by ZMS

  10. Aging-induced changes in brain regional serotonin receptor binding: Effect of Carnosine.

    Science.gov (United States)

    Banerjee, S; Poddar, M K

    2016-04-05

    Monoamine neurotransmitter, serotonin (5-HT) has its own specific receptors in both pre- and post-synapse. In the present study the role of carnosine on aging-induced changes of [(3)H]-5-HT receptor binding in different brain regions in a rat model was studied. The results showed that during aging (18 and 24 months) the [(3)H]-5-HT receptor binding was reduced in hippocampus, hypothalamus and pons-medulla with a decrease in their both Bmax and KD but in cerebral cortex the [(3)H]-5-HT binding was increased with the increase of its only Bmax. The aging-induced changes in [(3)H]-5-HT receptor binding with carnosine (2.0 μg/kg/day, intrathecally, for 21 consecutive days) attenuated in (a) 24-month-aged rats irrespective of the brain regions with the attenuation of its Bmax except hypothalamus where both Bmax and KD were significantly attenuated, (b) hippocampus and hypothalamus of 18-month-aged rats with the attenuation of its Bmax, and restored toward the [(3)H]-5-HT receptor binding that observed in 4-month-young rats. The decrease in pons-medullary [(3)H]-5-HT binding including its Bmax of 18-month-aged rats was promoted with carnosine without any significant change in its cerebral cortex. The [(3)H]-5-HT receptor binding with the same dosages of carnosine in 4-month-young rats (a) increased in the cerebral cortex and hippocampus with the increase in their only Bmax whereas (b) decreased in hypothalamus and pons-medulla with a decrease in their both Bmax and KD. These results suggest that carnosine treatment may (a) play a preventive role in aging-induced brain region-specific changes in serotonergic activity (b) not be worthy in 4-month-young rats in relation to the brain regional serotonergic activity. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Imaging dopamine and opiate receptors in the human brain in health and disease

    International Nuclear Information System (INIS)

    Wagner, H.N. Jr.; Dannals, R.F.; Frost, J.J.

    1986-01-01

    Chemical activity accompanies mental activity, but only recently has it been possible to begin to examine its nature. In 1983 the first imaging of a neuroreceptor in the human brain was accomplished with carbon-11 methyl spipeone, a ligand that binds preferentially to dopamine-2 receptors, 80% of which are located in the caudate nucleus and putamen. Quantitative imaging of serotonin-2, opiate, benzodiazapine and muscarinic cholinergic receptors has subsequently been accomplished. In studies of normal men and women, it has been found that dopamine and serotonin receptor activity decreases dramatically with age, such a decrease being more pronounced in men than in women and greater in the case of dopamine receptors than serotonin-2 receptors. Preliminary studies in patients with neuropsychiatric disorders suggests that dopamine-2 receptor activity is diminished in the caudate nucleus of patients with Huntington's disease. Positron tomography permits quantitative assay of picomolar quantities of neuroreceptors within the living human brain. Studies of patients with Parkinson's disease, Alzheimer's disease, depression, anxiety, schizophrenia, acute and chronic pain states and drug addiction are now in progress

  12. Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation.

    Science.gov (United States)

    Tudurí, Eva; Beiroa, Daniel; Stegbauer, Johannes; Fernø, Johan; López, Miguel; Diéguez, Carlos; Nogueiras, Rubén

    2016-11-01

    Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of α2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in α2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on β-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Adenosine A2A Receptors Modulate Acute Injury and Neuroinflammation in Brain Ischemia

    Directory of Open Access Journals (Sweden)

    Felicita Pedata

    2014-01-01

    Full Text Available The extracellular concentration of adenosine in the brain increases dramatically during ischemia. Adenosine A2A receptor is expressed in neurons and glial cells and in inflammatory cells (lymphocytes and granulocytes. Recently, adenosine A2A receptor emerged as a potential therapeutic attractive target in ischemia. Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia the early massive increase of extracellular glutamate is followed by activation of resident immune cells, that is, microglia, and production or activation of inflammation mediators. Proinflammatory cytokines, which upregulate cell adhesion molecules, exert an important role in promoting recruitment of leukocytes that in turn promote expansion of the inflammatory response in ischemic tissue. Protracted neuroinflammation is now recognized as the predominant mechanism of secondary brain injury progression. A2A receptors present on central cells and on blood cells account for important effects depending on the time-related evolution of the pathological condition. Evidence suggests that A2A receptor antagonists provide early protection via centrally mediated control of excessive excitotoxicity, while A2A receptor agonists provide protracted protection by controlling massive blood cell infiltration in the hours and days after ischemia. Focus on inflammatory responses provides for adenosine A2A receptor agonists a wide therapeutic time-window of hours and even days after stroke.

  14. Benzodiazepine receptor turnover in embryonic chick brain and spinal cord cell cultures

    International Nuclear Information System (INIS)

    Borden, L.A.

    1985-01-01

    The turnover (synthesis and degradation) of the benzodiazepine receptor (BZD-R) in embryonic chick brain and spinal cord cell cultures was monitored using flunitrazepam (GNZM) as a photoaffinity label. To measure BZD-R appearance, intact cell cultures were incubated with 100 nM RNZM and irradiated with ultraviolet light; this process, referred to as photoinactivation, resulted in a 75% decrease in the subsequent reversible binding of 5 nM [ 3 H]FNZM. Following photoinactivation, [ 3 H]FNZM binding sites reappeared at a rate of 6 +/- 1.5%/hour (n = 7) in brain cultures and at 8%/hour (n = 2) in spinal cord cultures. Reappearance reflects de novo receptors synthesis. To examine the degradation of existing receptors, cultures were photolabeled with 5 nM [ 3 H]FNZM, washed, and then the decrease in cell-associated radioactivity, or the efflux of radioactivity into the medium, was monitored. The released radioactivity did not comigrate with authentic FNZM on thin-layer-chromatographs, indicating that release did not represent dissociation of ligand from the photolabeled receptor. The BZD-R appears to be degraded by an energy-dependent, non-lysosomal pathway. These experiments represent the first direct examination of the turnover of a neurotransmitter receptor localized to the central nervous system; this information will be valuable in elucidating the mechanisms by which receptor levels are altered following chronic drug treatment

  15. Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier

    Directory of Open Access Journals (Sweden)

    van Doorn Ruben

    2012-06-01

    Full Text Available Abstract Background The sphingosine 1-phosphate (S1P receptor modulator FTY720P (Gilenya® potently reduces relapse rate and lesion activity in the neuroinflammatory disorder multiple sclerosis. Although most of its efficacy has been shown to be related to immunosuppression through the induction of lymphopenia, it has been suggested that a number of its beneficial effects are related to altered endothelial and blood–brain barrier (BBB functionality. However, to date it remains unknown whether brain endothelial S1P receptors are involved in the maintenance of the function of the BBB thereby mediating immune quiescence of the brain. Here we demonstrate that the brain endothelial receptor S1P5 largely contributes to the maintenance of brain endothelial barrier function. Methods We analyzed the expression of S1P5 in human post-mortem tissues using immunohistochemistry. The function of S1P5 at the BBB was assessed in cultured human brain endothelial cells (ECs using agonists and lentivirus-mediated knockdown of S1P5. Subsequent analyses of different aspects of the brain EC barrier included the formation of a tight barrier, the expression of BBB proteins and markers of inflammation and monocyte transmigration. Results We show that activation of S1P5 on cultured human brain ECs by a selective agonist elicits enhanced barrier integrity and reduced transendothelial migration of monocytes in vitro. These results were corroborated by genetically silencing S1P5 in brain ECs. Interestingly, functional studies with these cells revealed that S1P5 strongly contributes to brain EC barrier function and underlies the expression of specific BBB endothelial characteristics such as tight junctions and permeability. In addition, S1P5 maintains the immunoquiescent state of brain ECs with low expression levels of leukocyte adhesion molecules and inflammatory chemokines and cytokines through lowering the activation of the transcription factor NFκB. Conclusion Our

  16. Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Vida Naderi

    2015-02-01

    Full Text Available Objective(s:Estrogen (E2 has neuroprotective effects on blood-brain-barrier (BBB after traumatic brain injury (TBI. In order to investigate the roles of estrogen receptors (ERs in these effects, ER-α antagonist (MPP and, ER-β antagonist (PHTPP, or non-selective estrogen receptors antagonist (ICI 182780 were administered. Materials and Methods: Ovariectomized rats were divided into 10 groups, as follows: Sham, TBI, E2, oil, MPP+E2, PHTPP+E2, MPP+PHTPP+E2, ICI+E2, MPP, and DMSO. E2 (33.3 µg/Kg or oil were administered 30 min after TBI. 1 dose (150 µg/Kg of each of MPP, PHTPP, and (4 mg/kg ICI182780 was injected two times, 24 hr apart, before TBI and estrogen treatment. BBB disruption (Evans blue content and brain edema (brain water content evaluated 5 hr and 24 hr after the TBI were evaluated, respectively. Results: The results showed that E2 reduced brain edema after TBI compared to vehicle (P

  17. The Transferrin Receptor at the Blood-Brain Barrier - exploring the possibilities for brain drug delivery

    NARCIS (Netherlands)

    Visser, Corine

    2005-01-01

    There are many diseases of the central nervous system (CNS), like Parkinson's disease, Alzheimer's disease, depression, schizophrenia, epilepsy, migraine headache, and HIV infection in the brain. However, treatment is difficult since many drugs cannot reach the brain in sufficient quantities due to

  18. Channel opening of gamma-aminobutyric acid receptor from rat brain: molecular mechanisms of the receptor responses.

    Science.gov (United States)

    Cash, D J; Subbarao, K

    1987-12-01

    The function of gamma-aminobutyric acid (GABA) receptors, which mediate transmembrane chloride flux, can be studied by use of 36Cl- isotope tracer with membrane from mammalian brain by quench-flow technique, with reaction times that allow resolution of the receptor desensitization rates from the ion flux rates. The rates of chloride exchange into the vesicles in the absence and presence of GABA were characterized with membrane from rat cerebral cortex. Unspecific 36Cl- influx was completed in three phases of ca. 3% (t 1/2 = 0.6 s), 56% (t 1/2 = 82 s), and 41% (t 1/2 = 23 min). GABA-mediated, specific chloride exchange occurred with 6.5% of the total vesicular internal volume. The GABA-dependent 36Cl- influx proceeded in two phases, each progressively slowed by desensitization. The measurements supported the presence of two distinguishable active GABA receptors on the same membrane mediating chloride exchange into the vesicles with initial first-order rate constants of 9.5 s-1 and 2.3 s-1 and desensitizing with first-order rate constants of 21 s-1 and 1.4 s-1, respectively, at saturation. The half-response concentrations were similar for both receptors, 150 microM and 114 microM GABA for desensitization and 105 microM and 82 microM for chloride exchange, for the faster and slower desensitizing receptors, respectively. The two receptors were present in the activity ratio of ca. 4/1, similar to the ratio of "low-affinity" to "high-affinity" GABA sites found in ligand binding experiments. The desensitization rates have a different dependence on GABA concentration than the channel-opening equilibria.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Localization of insulin receptor mRNA in rat brain by in situ hybridization

    International Nuclear Information System (INIS)

    Marks, J.L.; Porte, D. Jr.; Stahl, W.L.; Baskin, D.G.

    1990-01-01

    Insulin receptor mRNA was demonstrated in rat brain slices by in situ hybridization with three 35 S-oligonucleotide probes and contact film autoradiography. Specificity was confirmed by showing that (a) excess unlabeled probe abolished the signal, (b) an oligonucleotide probe for rat neuropeptide Y mRNA showed a different distribution of hybridization signal, and (c) the distribution of insulin receptor binding was consistent with the distribution of insulin receptor mRNA. Insulin receptor mRNA was most abundant in the granule cell layers of the olfactory bulb, cerebellum and dentate gyrus, in the pyramidal cell body layers of the pyriform cortex and hippocampus, in the choroid plexus and in the arcuate nucleus of the hypothalamus

  20. Receptor macroautoradiography of 3H-spiroperidol binding in rat brain

    International Nuclear Information System (INIS)

    Mori, Hirofumi; Shiba, Kazuhiro; Tsuji, Shiro; Matsuda, Hiroshi; Hisada, Kinichi; Kojima, Kazuhiko

    1985-01-01

    The kinetic and pharmacological characteristics of 3 H-spiroperidol binding sites were studied in slide mounted sections of rat forebrain, and optical binding conditions were defined. Using the receptor macroautoradiographic techniques with tritium-sensitive LKB sheet film, the distribution of dopamine (D 2 ) receptor was determined in slices including striatum of rat brain. The autoradiograms were analyzed using Video Digitizer System combined with video camera and minicomputer, and the subtraction images were obtained. These studies suggest that this quantitative receptor macroautoradiography might be useful in the explanation of etiology in the field of neuro-psychiatric diseases and the fundamental studies of positron emission computed tomography, since this method has several advantages over in vivo autoradiography and in vitro receptor assay. (author)

  1. Purification and characterization of mu-specific opioid receptor from rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa, J.; Cho, T.M.; Ge, B.L.; Loh, H.H.

    1986-03-05

    A mu-specific opioid receptor was purified to apparent homogeneity from rat brain membranes by 6-succinylmorphine affinity chromatography, Ultrogel filtration, wheat germ agglutinin affinity chromatography, and isoelectric focusing. The purified receptor had a molecular weight of 58,000 as determined by polyacrylamide gel electrophoresis, and was judged to be homogeneous by the following criteria: (1) a single band on the SDS gel; and (2) a specific opioid binding activity of 17,720 pmole/mg protein, close to the theoretical value. In addition, the 58,000 molecular weight value agrees closely with that determined by covalently labelling purified receptor with bromoacetyl-/sup 3/H-dihydromorphine or with /sup 125/I-beta-endorphin and dimethyl suberimidate. To their knowledge, this is the first complete purification of an opioid receptor that retains its ability to bind opiates.

  2. Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities.

    Science.gov (United States)

    Staley, J K; Mash, D C

    1996-10-01

    The mesolimbic dopaminergic system plays a primary role in mediating the euphoric and rewarding effects of most abused drugs. Chronic cocaine use is associated with an increase in dopamine neurotransmission resulting from the blockade of dopamine uptake and is mediated by the activation of dopamine receptors. Recent studies have suggested that the D3 receptor subtype plays a pivotal role in the reinforcing effects of cocaine. The D3 receptor-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) is a reinforcer in rhesus monkeys trained to self-administer cocaine, but not in cocainenaive monkeys. In vitro autoradiographic localization of [3H]-(+)-7-OH-DPAT binding in the human brain demonstrated that D3 receptors were prevalent and highly localized over the ventromedial sectors of the striatum. Pharmacological characterization of [3H]-(+)-7-OH-DPAT binding to the human nucleus accumbens demonstrated a rank order of potency similar to that observed for binding to the cloned D3 receptor expressed in transfected cell lines. Region-of-interest analysis of [3H]-(+)-7-OH-DPAT binding to the D3 receptor demonstrated a one- to threefold elevation in the number of binding sites over particular sectors of the striatum and substantia nigra in cocaine overdose victims as compared with age-matched and drug-free control subjects. The elevated number of [3H]-(+)-7-OH-DPAT binding sites demonstrates that adaptive changes in the D3 receptor in the reward circuitry of the brain are associated with chronic cocaine abuse. These results suggest that the D3 receptor may be a useful target for drug development of anticocaine medications.

  3. Guanine nucleotide-binding protein regulation of melatonin receptors in lizard brain

    International Nuclear Information System (INIS)

    Rivkees, S.A.; Carlson, L.L.; Reppert, S.M.

    1989-01-01

    Melatonin receptors were identified and characterized in crude membrane preparations from lizard brain by using 125 I-labeled melatonin ( 125 I-Mel), a potent melatonin agonist. 125 I-Mel binding sites were saturable; Scatchard analysis revealed high-affinity and lower affinity binding sites, with apparent K d of 2.3 ± 1.0 x 10 -11 M and 2.06 ± 0.43 x 10 -10 M, respectively. Binding was reversible and inhibited by melatonin and closely related analogs but not by serotonin or norepinephrine. Treatment of crude membranes with the nonhydrolyzable GTP analog guanosine 5'-[γ-thio]triphosphate (GTP[γS]), significantly reduced the number of high-affinity receptors and increased the dissociation rate of 125 I-Mel from its receptor. Furthermore, GTP[γS] treatment of ligand-receptor complexes solubilized by Triton X-100 also led to a rapid dissociation of 125 I-Mel from solubilized ligand-receptor complexes. Gel filtration chromatography of solubilized ligand-receptor complexes revealed two major peaks of radioactivity corresponding to M r > 400,000 and M r ca. 110,000. This elution profile was markedly altered by pretreatment with GTP[γS] before solubilization; only the M r 110,000 peak was present in GTP[γS]-pretreated membranes. The results strongly suggest that 125 I-mel binding sites in lizard brain are melatonin receptors, with agonist-promoted guanine nucleotide-binding protein (G protein) coupling and that the apparent molecular size of receptors uncoupled from G proteins is about 110,000

  4. The effects of age on dopamine receptors measured by positron tomography in the living human brain

    International Nuclear Information System (INIS)

    Wong, D.F.; Wagner, E.N. Jr.; Dannals, R.F.

    1984-01-01

    C-11 n-methylspiperone has been used to measure dopamine (D2) receptors in the caudate and putamen of 30 normal persons. In vitro studies in rodent brain revealed a high affinity for dopamine (D2) receptors and five fold less for serotonin (S2) receptors. In vivo drug competition studies in rodents demonstrated that 90% of striatal binding is to dopamine receptors. In the frontal cortex, the majority of receptor binding is to serotonin receptors. Thirty normal volunteers aged 19 to 73 years were screened for normality by medical, neurological and neuropsychological examinations. Positron tomography was performed serially for 2 hours after injection. In 10 subjects there was good agreement between activity in arterial samples and that in venous samples from a heated hand. Binding in the dopamine rich caudate and putamen progressively increased while binding in the dopamine poor cerebellum decreased. The dopamine receptor density was estimated by the ratio of the caudate-to-cerebellar mean counts/pixel (Ca/Cb) and putamen-to-cerebellar mean counts/pixel (Pu/Cb). The ratios (Ca/Cb, Pu/Cb) increased linearly with time (r>0.95) for each subject. There was a decrease (Ca/Cb) with age (0.8%/yr) that could be approximated with a linear fit: (Ca/Cb = -.02 age + 3.92, r=.6). For the 21 males alone, the decrease was (1.1%/yr, r=.7 , p <.01), while for the 9 females there was no significant decrease with age. Similar findings were noted in the putamen. This decline in dopamine receptor density with age has been reported in rodent and human autopsy studies, but never before in the living human brain

  5. GABA and benzodiazepine receptors in the gerbil brain after transient ischemia: demonstration by quantitative receptor autoradiography

    International Nuclear Information System (INIS)

    Onodera, H.; Sato, G.; Kogure, K.

    1987-01-01

    Quantitative receptor autoradiography was used to measure the binding of gamma-aminobutyric acid (GABA) and benzodiazepine receptors after ischemia by means of transient occlusion of bilateral common carotid arteries in the gerbil. [ 3 H]Muscimol was used to label the GABAA receptors and [ 3 H]flunitrazepam to label central type benzodiazepine receptors. In the superolateral convexities of the frontal cortices, [ 3 H]muscimol binding was increased in 60% of the animals killed 3 days after ischemia, and decreased in 67% of the animals killed 27 days after ischemia. Twenty-seven days after ischemia, [ 3 H]flunitrazepam binding in the substantia nigra pars reticulata increased to 252% of the control, though the increase in [ 3 H]muscimol binding was not significant. In the dorsolateral region of the caudate putamen, marked neuronal necrosis and depletion of both [ 3 H]muscimol and [ 3 H]flunitrazepam binding sites were observed 27 days after ischemia, the ventromedial region being left intact. In spite of the depletion of pyramidal cells in the CA1 region of the hippocampus, both [ 3 H]muscimol and [ 3 H]flunitrazepam binding sites were preserved 27 days after ischemia. Since our previous study revealed that adenosine A1 binding sites were depleted in the CA1 subfield of the hippocampus after ischemia correlating with neuronal damage, GABAA and benzodiazepine receptors may not be distributed predominantly on the pyramidal cells in the CA1 region

  6. Sexually dimorphic development and binding characteristics of NMDA receptors in the brain of the platyfish

    Science.gov (United States)

    Flynn, K. M.; Schreibman, M. P.; Yablonsky-Alter, E.; Banerjee, S. P.

    1999-01-01

    This study investigated age- and gender-specific variations in properties of the glutamate N-methyl-d-aspartate receptor (NMDAR) in a freshwater teleost, the platyfish (Xiphophorus maculatus). Prior localization of the immunoreactive (ir)-R1 subunit of the NMDAR protein (R1) in cells of the nucleus olfactoretinalis (NOR), a primary gonadotropin-releasing hormone (GnRH)-containing brain nucleus in the platyfish, suggests that NMDAR, as in mammals, is involved in modulation of the platyfish brain-pituitary-gonad (BPG) axis. The current study shows that the number of cells in the NOR displaying ir-R1 is significantly increased in pubescent and mature female platyfish when compared to immature and senescent animals. In males, there is no significant change in ir-R1 expression in the NOR at any time in their lifespan. The affinity of the noncompetitive antagonist ((3)H)MK-801 for the NMDAR is significantly increased in pubescent females while maximum binding of ((3)H)MK-801 to the receptor reaches a significant maximum in mature females. In males, both MK-801 affinity and maximum binding remain unchanged throughout development. This is the first report of gender differences in the association of NMDA receptors with neuroendocrine brain areas during development. It is also the first report to suggest NMDA receptor involvement in the development of the BPG axis in a nonmammalian vertebrate. Copyright 1999 Academic Press.

  7. The nuclear receptor PPARγ as a therapeutic target for cerebrovascular and brain dysfunction in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Nektaria Nicolakakis

    2010-05-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are ligand-activated nuclear transcription factors that regulate peripheral lipid and glucose metabolism. Three subtypes make up the PPAR family (α, γ, β/δ, and synthetic ligands for PPARα (fibrates and PPARγ (Thiazolidinediones, TZDs are currently prescribed for the respective management of dyslipidemia and type 2 diabetes. In contrast to the well characterized action of PPARs in the periphery, little was known about the presence or function of these receptors in the brain and cerebral vasculature, until fairly recently. Indeed, research in the last decade has uncovered these receptors in most brain cell types, and has shown that their activation, particularly that of PPARγ, is implicated in normal brain and cerebrovascular physiology, and confers protection under pathological conditions. Notably, accumulating evidence has highlighted the therapeutic potential of PPARγ ligands in the treatment of brain disorders such as Alzheimer’s disease (AD, leading to the testing of the TZDs pioglitazone and rosiglitazone in AD clinical trials. This review will focus on the benefits of PPARγ agonists for vascular, neuronal and glial networks, and assess the value of these compounds as future AD therapeutics in light of evidence from transgenic mouse models and recent clinical trials.

  8. Kinetics of Transferrin and Transferrin-Receptor during Iron Transport through Blood Brain Barrier

    Science.gov (United States)

    Khan, Aminul; Liu, Jin; Dutta, Prashanta

    2017-11-01

    Transferrin and its receptors play an important role during the uptake and transcytosis of iron by blood brain barrier (BBB) endothelial cells to maintain iron homeostasis in BBB endothelium and brain. In the blood side of BBB, ferric iron binds with the apo-transferrin to form holo-transferrin which enters the endothelial cell via transferrin receptor mediated endocytosis. Depending on the initial concentration of iron inside the cell endocytosed holo-transferrin can either be acidified in the endosome or exocytosed through the basolateral membrane. Acidification of holo-transferrin in the endosome releases ferrous irons which may either be stored and used by the cell or transported into brain side. Exocytosis of the holo-transferrin through basolateral membrane leads to transport of iron bound to transferrin into brain side. In this work, kinetics of internalization, recycling and exocytosis of transferrin and its receptors are modeled by laws of mass action during iron transport in BBB endothelial cell. Kinetic parameters for the model are determined by least square analysis. Our results suggest that the cell's initial iron content determines the extent of the two possible iron transport pathways, which will be presented in this talk Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM122081.

  9. Agonist and antagonist binding to rat brain muscarinic receptors: influence of aging

    International Nuclear Information System (INIS)

    Gurwitz, D.; Egozi, Y.; Henis, Y.I.; Kloog, Y.; Sokolovsky, M.

    1987-01-01

    The objective of the present study was to determine the binding properties of muscarinic receptors in six brain regions in mature and old rats of both sexes by employing direct binding of [ 3 H]-antagonist as well as of the labeled natural neurotransmitter, [ 3 H]-acetylcholine [( 3 H]-AcCh). In addition, age-related factors were evaluated in the modulation processes involved in agonist binding. The results indicate that as the rat ages the density of the muscarinic receptors is altered differently in the various brain regions: it is decreased in the cerebral cortex, hippocampus, striatum and olfactory bulb of both male and female rats, but is increased (58%) in the brain stem of senescent males while no significant change is observed for females. The use of the highly sensitive technique measuring direct binding of [ 3 H]-AcCh facilitated the separate detection of age-related changes in the two classes (high- and low-affinity) of muscarinic agonist binding sites. In old female rats the density of high-affinity [ 3 H]-AcCh binding sites was preserved in all tissues studied, indicating that the decreases in muscarinic receptor density observed with [ 3 H]-antagonist represent a loss of low-affinity agonist binding sites. In contrast, [ 3 H]-AcCh binding is decreased in the hypothalamus and increased in the brain stem of old male rats. These data imply sexual dimorphism of the aging process in central cholinergic mechanisms

  10. [Studying specific effects of nootropic drugs on glutamate receptors in the rat brain].

    Science.gov (United States)

    Firstova, Iu Iu; Vasil'eva, E V; Kovalev, G I

    2011-01-01

    The influence of nootropic drugs of different groups (piracetam, phenotropil, nooglutil, noopept, semax, meclofenoxate, pantocalcine, and dimebon) on the binding of the corresponding ligands to AMPA, NMDA, and mGlu receptors of rat brain has been studied by the method of radio-ligand binding in vitro. It is established that nooglutil exhibits pharmacologically significant competition with a selective agonist of AMPA receptors ([G-3H]Ro 48-8587) for the receptor binding sites (with IC50 = 6.4 +/- 0.2 microM), while the competition of noopept for these receptor binding sites was lower by an order of magnitude (IC50 = 80 +/- 5.6 microM). The heptapeptide drug semax was moderately competitive with [G-3H]LY 354740 for mGlu receptor sites (IC50 = 33 +/- 2.4 microM). Dimebon moderately influenced the specific binding of the ligand of NMDA receptor channel ([G-3H]MK-801) at IC50 = 59 +/- 3.6 microM. Nootropic drugs of the pyrrolidone group (piracetam, phenotropil) as well as meclofenoxate, pantocalcine (pantogam) in a broad rage of concentrations (10(-4)-10(-10) M) did not affect the binding of the corresponding ligands to glutamate receptors (IC50 100 pM). Thus, the direct neurochemical investigation was used for the first time to qualitatively characterize the specific binding sites for nooglutil and (to a lower extent) noopept on AMPA receptors, for semax on metabotropic glutamate receptors, and for dimebon on the channel region of NMDA receptors. The results are indicative of a selective action of some nootropes on the glutamate family.

  11. TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.

    Science.gov (United States)

    Ji, Rui; Tian, Shifu; Lu, Helen J; Lu, Qingjun; Zheng, Yan; Wang, Xiaomin; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

    2013-12-15

    TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.

  12. Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain.

    Science.gov (United States)

    Stefanis, N C; Bresnick, J N; Kerwin, R W; Schofield, W N; McAllister, G

    1998-01-01

    The D4 dopamine (DA) receptor has been proposed to be a target for the development of a novel antipsychotic drug based on its pharmacological and distribution profile. There is much interest in whether D4 DA receptor levels are altered in schizophrenia, but the lack of an available receptor subtype-specific radioligand made this difficult to quantitate. In this study, we examined whether D4 mRNA levels are altered in different brain regions of schizophrenics compared to controls. Ribonuclease protection assays were carried out on total RNA samples isolated postmortem from frontal cortex and caudate brain regions of schizophrenics and matched controls. 32P-labelled RNA probes to the D4 DA receptor and to the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (G3PDH), were hybridised with the RNA samples, digested with ribonucleases to remove unhybridised probe, and separated on 6% sequencing gels. Densitometer analysis on the subsequent autoradiogams was used to calculate the relative optical density of D4 mRNA compared to G3PDH mRNA. Statistical analysis of the data revealed a 3-fold higher level (P<0.011) of D4 mRNA in the frontal cortex of schizophrenics compared to controls. No increase was seen in caudate. D4 receptors could play a role in mediating dopaminergic activity in frontal cortex, an activity which may be malfunctioning in schizophrenia.

  13. Targeting immunoliposomes to transferrin receptors on brain capillary endothelial cells as a mean for cargo transport across the blood-brain barrier

    DEFF Research Database (Denmark)

    Johnsen, Kasper Bendix; Larsen, Annette Burkhart; Bruun, Jonas

    2016-01-01

    Brain capillary endothelial cells (BCECs) express transferrin receptors as opposed to endothelial cells of any organ in the remaining body, suggesting that targeting to the transferrin receptors as a reasonable strategy for delivering drugs to the CNS. However, as the intracellular trafficking...

  14. Potentiated antibodies to mu-opiate receptors: effect on integrative activity of the brain.

    Science.gov (United States)

    Geiko, V V; Vorob'eva, T M; Berchenko, O G; Epstein, O I

    2003-01-01

    The effect of homeopathically potentiated antibodies to mu-receptors (10(-100) wt %) on integrative activity of rat brain was studied using the models of self-stimulation of the lateral hypothalamus and convulsions produced by electric current. Electric current was delivered through electrodes implanted into the ventromedial hypothalamus. Single treatment with potentiated antibodies to mu-receptors increased the rate of self-stimulation and decreased the threshold of convulsive seizures. Administration of these antibodies for 7 days led to further activation of the positive reinforcement system and decrease in seizure thresholds. Distilled water did not change the rate of self-stimulation and seizure threshold.

  15. Autoradiographic visualization of insulin-like growth factor-II receptors in rat brain

    International Nuclear Information System (INIS)

    Mendelsohn, L.G.; Kerchner, G.A.; Clemens, J.A.; Smith, M.C.

    1986-01-01

    The documented presence of IGF-II in brain and CSF prompted us to investigate the distribution of receptors for IGF-II in rat brain slices. Human 125 -I-IGF-II (10 pM) was incubated for 16 hrs at 4 0 C with slide-mounted rat brain slices in the absence and presence of unlabeled human IGF-II (67 nM) or human insulin (86 nM). Slides were washed, dried, and exposed to X-ray film for 4-7 days. The results showed dense labeling in the granular layers of the olfactory bulbs, deep layers of the cerebral cortex, pineal gland, anterior pituitary, hippocampus (pyramidal cells CA 1 -CA 2 and dentate gyrus), and the granule cell layers of the cerebellum. Unlabeled IGF-II eliminated most of the binding of these brain regions while insulin produced only a minimal reduction in the amount of 125 I-IGF-II bound. These results indicate that a specific neural receptor for IGS-II is uniquely distributed in rat brain tissue and supports the notion that this peptide might play an important role in normal neuronal functioning

  16. Changes in sensitivity of brain dopamine and serotonin receptors during long-term treatment with carbidine

    International Nuclear Information System (INIS)

    Zharkovskii, A.M.; Allikmets, L.K.; Chereshka, K.S.; Zharkovskaya, T.A.

    1986-01-01

    The authors study the state of the dopamine and serotonin receptors of the brain during chronic administration of carbidine to animals. Parts of the brain from two rats were pooled and binding of tritium-spiperone and tritium-LSD was determined. Statistical analysis of the data for apomorphine sterotypy was carried out and the Student's test was used for analysis of the remaining data. It is shown that after discontinuation of carbidine binding of tritium-spiperone and tritium-LSD in the cortex was reduced

  17. Opiate receptor binding in the brain of the seizure sensitive Mongolian gerbil (Meriones unguiculatus).

    Science.gov (United States)

    Lee, R J; Olsen, R W; Lomax, P; McCabe, R T; Wamsley, J K

    1984-12-01

    Opiate receptor binding was studied in seizure sensitive (SS) and seizure resistant (SR) strains of the Mongolian gerbil. Cryostat sections of the brain were labeled with [3H]-dihydromorphine, subjected to autoradiography and analysed by microdensitometry. SS gerbils, prior to seizure induction, demonstrated overall greater brain opiate binding when compared to SR animals. Immediately following a seizure, binding in the interpeduncular nucleus fell to levels found in SR animals. The increased opiate binding in the SS (pre-seizure) compared to SR gerbils could reflect a deficit of endogenous ligand which could underlie the seizure diathesis in the gerbil.

  18. Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

    Directory of Open Access Journals (Sweden)

    Andreas Stengel

    2017-04-01

    Full Text Available Corticotropin-releasing factor (CRF is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

  19. Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response.

    Science.gov (United States)

    Stengel, Andreas; Taché, Yvette F

    2017-01-01

    Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates-in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis-other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake) and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

  20. Physiology and physiopathology of central type Benzodiazepine receptors: Study in the monkey and in human brain using positron emission tomography

    International Nuclear Information System (INIS)

    Hantraye, P.

    1987-01-01

    A new non-invasive technique that allows to study in a living subject central type benzodiazepine receptors is developed. A combined approach is applied using a specific positron-emitting radiotracer for the in vivo labelling of the receptors and positron emission tomography allowing, by external detection, a quantitative determination of tissue radioactivity. The radioligand used for the in vivo labelling of benzodiazepine receptors is the antagonist RO 15-1788 labelled with carbon 11. The various stages of the study are described: in vivo characterization in the monkey of central type benzodiazepine receptors; characterization of central type benzodiazepine receptors in human brain using selective molecules for the BZ1 benzodiazepine subclass; demonstration of the heterogeneity of central type benzodiazepine receptors in the brain; study of pathological alteration of benzodiazepine receptors in experimental epilepsy [fr

  1. Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

    Science.gov (United States)

    Ducrot, Charles; Fortier, Emmanuel; Bouchard, Claude; Rompré, Pierre-Paul

    2013-01-01

    Previous studies have shown that blockade of ventral tegmental area (VTA) glutamate N-Methyl-D-Aspartate (NMDA) receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VTA neurons, a fast and short lasting depolarization mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VTA neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VTA neuronal activity, we studied the effects of VTA AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for 2 h after bilateral VTA microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5 μl/side) and of a single dose (0.825 nmol/0.5 μl/side) of the NMDA antagonist, PPPA (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid). NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VTA sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected, respectively, into the anterior and posterior VTA. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VTA neurons, to

  2. Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

    Directory of Open Access Journals (Sweden)

    Charles eDucrot

    2013-10-01

    Full Text Available Previous studies have shown that blockade of ventral midbrain (VM glutamate N-Methyl-D-Aspartate (NMDA receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VM neurons, a fast and short lasting depolarisation mediated by a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VM neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VM neuronal activity, we studied the effects of VM AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for two hours after bilateral VM microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(fquinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5ul/side and of a single dose (0.825 nmol/0.5ul/side of the NMDA antagonist, PPPA (2R,4S-4-(3-Phosphonopropyl-2-piperidinecarboxylic acid. NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VM sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected respectively into the anterior and posterior VM. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VM neurons, to modulate

  3. Neurotransmitter Specific, Cellular-Resolution Functional Brain Mapping Using Receptor Coated Nanoparticles: Assessment of the Possibility

    Science.gov (United States)

    Forati, Ebrahim; Sabouni, Abas; Ray, Supriyo; Head, Brian; Schoen, Christian; Sievenpiper, Dan

    2015-01-01

    Receptor coated resonant nanoparticles and quantum dots are proposed to provide a cellular-level resolution image of neural activities inside the brain. The functionalized nanoparticles and quantum dots in this approach will selectively bind to different neurotransmitters in the extra-synaptic regions of neurons. This allows us to detect neural activities in real time by monitoring the nanoparticles and quantum dots optically. Gold nanoparticles (GNPs) with two different geometries (sphere and rod) and quantum dots (QDs) with different sizes were studied along with three different neurotransmitters: dopamine, gamma-Aminobutyric acid (GABA), and glycine. The absorption/emission spectra of GNPs and QDs before and after binding of neurotransmitters and their corresponding receptors are reported. The results using QDs and nanorods with diameter 25nm and aspect rations larger than three were promising for the development of the proposed functional brain mapping approach. PMID:26717196

  4. Brain aromatase (Cyp19A2) and estrogen receptors, in larvae and adult pejerrey fish Odontesthes bonariensis: Neuroanatomical and functional relations

    Science.gov (United States)

    Strobl-Mazzulla, P. H.; Lethimonier, C.; Gueguen, M.M.; Karube, M.; Fernandino, J.I.; Yoshizaki, G.; Patino, R.; Strussmann, C.A.; Kah, O.; Somoza, G.M.

    2008-01-01

    Although estrogens exert many functions on vertebrate brains, there is little information on the relationship between brain aromatase and estrogen receptors. Here, we report the cloning and characterization of two estrogen receptors, ?? and ??, in pejerrey. Both receptors' mRNAs largely overlap and were predominantly expressed in the brain, pituitary, liver, and gonads. Also brain aromatase and estrogen receptors were up-regulated in the brain of estradiol-treated males. In situ hybridization was performed to study in more detail, the distribution of the two receptors in comparison with brain aromatase mRNA in the brain of adult pejerrey. The estrogen receptors' mRNAs exhibited distinct but partially overlapping patterns of expression in the preoptic area and the mediobasal hypothalamus, as well as in the pituitary gland. Moreover, the estrogen receptor ??, but not ??, were found to be expressed in cells lining the preoptic recess, similarly as observed for brain aromatase. Finally, it was shown that the onset expression of brain aromatase and both estrogen receptors in the head of larvae preceded the morphological differentiation of the gonads. Because pejerrey sex differentiation is strongly influenced by temperature, brain aromatase expression was measured during the temperature-sensitive window and was found to be significantly higher at male-promoting temperature. Taken together these results suggest close neuroanatomical and functional relationships between brain aromatase and estrogen receptors, probably involved in the sexual differentiation of the brain and raising interesting questions on the origin (central or peripheral) of the brain aromatase substrate. ?? 2008 Elsevier Inc.

  5. Autoradiographic localization of putative nicotinic receptors in the rat brain using 125I-neuronal bungarotoxin

    International Nuclear Information System (INIS)

    Schulz, D.W.; Loring, R.H.; Aizenman, E.; Zigmond, R.E.

    1991-01-01

    Neuronal bungarotoxin (NBT), a snake venom neurotoxin, selectively blocks nicotinic receptors in many peripheral and central neuronal preparations. alpha-Bungarotoxin (alpha BT), on the other hand, a second toxin isolated from the venom of the same snake, is an ineffective nicotinic antagonist in most vertebrate neuronal preparations studied thus far. To examine central nicotinic receptors recognized by NBT, we have characterized the binding of 125I-labeled NBT (125I-NBT) to rat brain membranes and have mapped the distribution of 125I-NBT binding in brain sections using quantitative light microscopic autoradiography. The binding of 125I-NBT was found to be saturable, of high affinity, and heterogeneously distributed in the brain. Pharmacological studies suggested that more than one population of sites is labeled by 125I-NBT. For example, one component of 125I-NBT binding was also recognized by alpha BT, while a second component, not recognized by alpha BT, was recognized by the nicotinic agonist nicotine. The highest densities of these alpha BT-insensitive, nicotine-sensitive sites were found in the fasciculus retroflexus, the lateral geniculate nucleus, the medial terminal nucleus of the accessory optic tract, and the olivary pretectal nucleus. alpha BT-sensitive NBT binding sites were found in highest density in the lateral geniculate nucleus, the subthalamic nucleus, the dorsal tegmental nucleus, and the medial mammillary nucleus (lateral part). The number of brain regions with a high density of 125I-NBT binding sites, blocked either by alpha BT or by nicotine, is low when compared with results obtained using other approaches to studying the central distribution of nicotinic receptors, such as labeling with 3H-nicotine or labeling with cDNA probes to mRNAs coding for putative receptor subunits

  6. Discrete mapping of brain Mu and delta opioid receptors using selective peptides: Quantitative autoradiography, species differences and comparison with kappa receptors

    Energy Technology Data Exchange (ETDEWEB)

    Sharif, N.A.; Hughes, J. (Addenbrookes Hospital Site, Cambridge (England))

    1989-05-01

    The opioid peptides, (3H)DAGO and (3H)DPDPE, bound to rat and guinea pig brain homogenates with a high, nanomolar affinity and to a high density of mu and delta receptors, respectively. (3H)DAGO binding to mu receptors was competitively inhibited by unlabelled opioids with the following rank order of potency: DAGO greater than morphine greater than DADLE greater than naloxone greater than etorphine much greater than U50488 much greater than DPDPE. In contrast, (3H)DPDPE binding to delta receptors was inhibited by compounds with the following rank order of potency: DPDPE greater than DADLE greater than etorphine greater than dynorphin(1-8) greater than naloxone much greater than U50488 much greater than DAGO. These profiles were consistent with specific labelling of the mu and delta opioid receptors, respectively. In vitro autoradiographic techniques coupled with computer-assisted image analyses revealed a discrete but differential anatomical localization of mu and delta receptors in the rat and guinea pig brain. In general, mu and delta receptor density in the rat exceeded that in the guinea pig brain and differed markedly from that of kappa receptors in these species. However, while mu receptors were distributed throughout the brain with hotspots in the fore-, mid- and hindbrain of the two rodents, the delta sites were relatively diffusely distributed, and were mainly concentrated in the forebrain with particularly high levels within the olfactory bulb (OB), n. accumbens and striatum. Notable regions of high density of mu receptors in the rat and guinea pig brain were the accessory olfactory bulb, striatal patches and streaks, amygdaloid nuclei, ventral hippocampal subiculum and dentate gyrus, numerous thalamic nuclei, geniculate bodies, central grey, superior and inferior colliculi, solitary and pontine nuclei and s. nigra.

  7. Immuno-localization of galanin receptor-1 (GALR1) in rat brain

    International Nuclear Information System (INIS)

    Larm, J.M.; Gundlach, A.L.

    2002-01-01

    Full text: Galanin is expressed in discrete areas throughout the central nervous system and has several putative physiological actions including effects on hormone secretion, reproduction and cognition, via actions at multiple G-protein-coupled receptors. Currently, three galanin receptors - GalR1, -R2, -R3 - have been identified that differ in pharmacology, signalling and distribution. The distribution of [ 125 I]-galanin binding sites presumably represents multiple receptors and so the precise regional and cellular localization of each receptor subtype is unknown. This study examined the distribution in rat brain of GalR1 receptors by immunohistochemistry, using polyclonal antibodies raised against short peptide sequences from the third intracellular loop and the proximal C-terminal. Adult rats were deeply anaesthetized (pentobarbitone 60 mg/kg, ip.) and perfusion-fixed with 4% paraformaldehyde. Specific GalR1 immunoreactivity (IR) was detected in neurons in various brain regions including cells within the olfactory bulb, piriform cortex, dorsomedial thalamus, hypothalamus (PVN, SON, ARC), midbrain/pons (intense staining in ventrolateral/medial PAG) and medulla. The localization pattern was qualitatively similar with both antisera and was consistent with that observed for GalR1 mRNA in normal rat brain. Recent evidence also reveals that GalR1- mRNA and -IR levels are coordinately altered after neuronal stimulation. These studies demonstrate a method for the identification of GalR1-containing cells that should assist in better differentiating the phenotype of galanin-receptive neurons. Copyright (2002) Australian Neuroscience Society

  8. Notch receptor expression in neurogenic regions of the adult zebrafish brain.

    Directory of Open Access Journals (Sweden)

    Vanessa de Oliveira-Carlos

    Full Text Available The adult zebrash brain has a remarkable constitutive neurogenic capacity. The regulation and maintenance of its adult neurogenic niches are poorly understood. In mammals, Notch signaling is involved in stem cell maintenance both in embryonic and adult CNS. To better understand how Notch signaling is involved in stem cell maintenance during adult neurogenesis in zebrafish we analysed Notch receptor expression in five neurogenic zones of the adult zebrafish brain. Combining proliferation and glial markers we identified several subsets of Notch receptor expressing cells. We found that 90 [Formula: see text] of proliferating radial glia express notch1a, notch1b and notch3. In contrast, the proliferating non-glial populations of the dorsal telencephalon and hypothalamus rarely express notch3 and about half express notch1a/1b. In the non-proliferating radial glia notch3 is the predominant receptor throughout the brain. In the ventral telencephalon and in the mitotic area of the optic tectum, where cells have neuroepithelial properties, notch1a/1b/3 are expressed in most proliferating cells. However, in the cerebellar niche, although progenitors also have neuroepithelial properties, only notch1a/1b are expressed in a high number of PCNA [Formula: see text] cells. In this region notch3 expression is mostly in Bergmann glia and at low levels in few PCNA [Formula: see text] cells. Additionally, we found that in the proliferation zone of the ventral telencephalon, Notch receptors display an apical high to basal low gradient of expression. Notch receptors are also expressed in subpopulations of oligodendrocytes, neurons and endothelial cells. We suggest that the partial regional heterogeneity observed for Notch expression in progenitor cells might be related to the cellular diversity present in each of these neurogenic niches.

  9. Localization of receptors for bombesin-like peptides in the rat brain

    International Nuclear Information System (INIS)

    Moody, T.W.; Getz, R.; O'Donohue, T.L.; Rosenstein, J.M.

    1988-01-01

    BN-like peptides and receptors are present in discrete areas of the mammalian brain. By radioimmunoassay, endogenous BN/GRP, neuromedin B, and ranatensin-like peptides are present in the rat brain. High-to-moderate concentrations of BN/GRP are present in the rat hypothalamus and thalamus, whereas moderate-to-high densities of neuromedin B and ranatensin-like peptides are present in the olfactory bulb and hippocampus, as well as in the hypothalamus and thalamus. While the distribution of neuromedin B and ranatensin-like peptides appears similar, it is distinct from that of BN/GRP. When released from CNS neurons, these peptides may interact with receptors for BN-like peptides. BN, GRP, ranatensin, and neuromedin B inhibit specific [ 125 I-Tyr4]BN binding with high affinity. By use of in vitro autoradiographic techniques to detect binding of [ 125 I-Tyr4]BN to receptors for BN-like peptides, high grain densities were found in the olfactory bulb and tubercle, the nucleus accumbens, the suprachiasmatic and paraventricular nucleus of the hypothalamus, the central medial and paraventricular thalamic nuclei, the hippocampus, the dentate gyrus, and the amygdala of the rat brain. Some of these receptors may be biologically active and mediate the biological effects of BN-like peptides. For example, when BN is directly injected into the nucleus accumbens, pronounced grooming results and the effects caused by BN are reversed by spantide and [D-Phe12]BN. Thus, the putative BN receptor antagonists may serve as useful agents to investigate the biological significance of BN-like peptides in the CNS

  10. Effects of visual deprivation during brain development on expression of AMPA receptor subunits in rat’s hippocampus

    Directory of Open Access Journals (Sweden)

    Sayyed Alireza Talaei

    2015-06-01

    Conclusion: Dark rearing of rats during critical period of brain development changes the relative expression and also arrangement of both AMPA receptor subunits, GluR1 and GluR2 in the hippocampus, age dependently.

  11. Involvement of CCR-2 chemokine receptor activation in ischemic preconditioning and postconditioning of brain in mice.

    Science.gov (United States)

    Rehni, Ashish K; Singh, Thakur Gurjeet

    2012-10-01

    The present study has been designed to investigate the potential role of CCR-2 chemokine receptor in ischemic preconditioning as well as postconditioning induced reversal of ischemia-reperfusion injury in mouse brain. Bilateral carotid artery occlusion of 17 min followed by reperfusion for 24h was employed in present study to produce ischemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using elevated plus-maze test and Morris water maze test. Rota rod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired memory and motor co-ordination. Three preceding episodes of bilateral carotid artery occlusion for 1 min and reperfusion of 1 min were employed to elicit ischemic preconditioning of brain, while three episodes of bilateral carotid artery occlusion for 10s and reperfusion of 10s immediately after the completion of were employed to elicit ischemic postconditioning of brain. Both prior ischemic preconditioning as well as ischemic postconditioning immediately after global cerebral ischemia prevented markedly ischemia-reperfusion-induced cerebral injury as measured in terms of infarct size, loss of memory and motor coordination. RS 102895, a selective CCR-2 chemokine receptor antagonist, attenuated the neuroprotective effect of both the ischemic preconditioning as well as postconditioning. It is concluded that the neuroprotective effect of both ischemic preconditioning as well as ischemic postconditioning may involve the activation of CCR-2 chemokine receptors. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Molecular mechanisms of the synergy between cysteinyl-leukotrienes and receptor tyrosine kinase growth factors on human bronchial fibroblast proliferation

    Directory of Open Access Journals (Sweden)

    Hajime Yoshisue

    2006-12-01

    Full Text Available We have reported that cysteinyl-leukotrienes (cys-LTs synergise not only with epidermal growth factor (EGF but also with platelet-derived growth factor (PDGF and fibroblast growth factor (FGF to induce mitogenesis in human bronchial fibroblasts. We now describe the molecular mechanisms underlying this synergism. Mitogenesis was assessed by incorporation of [3H]thymidine into DNA and changes in protein phosphorylation by Western blotting. Surprisingly, no CysLT receptor antagonists (MK-571, montelukast, BAY u9773 prevented the synergistic mitogenesis. LTD4 did not cause phosphorylation of EGFR nor did it augment EGF-induced phosphorylation of EGFR, and the synergy between LTD4 and EGF was not blocked by the metalloproteinase inhibitor GM6001 or by an HB-EGF neutralising antibody. The EGFR-selective kinase inhibitor, AG1478, suppressed the synergy by LTD4 and EGF, but had no effect on the synergy with PDGF and FGF. While inhibitors of mitogen-activated protein kinase, phosphatidylinositol 3-kinase and protein kinase C (PKC prevented the synergy, these drugs also inhibited mitogenesis elicited by EGF alone. In contrast, pertussis toxin (PTX efficiently inhibited the potentiating effect of LTD4 on EGF-induced mitogenesis, as well as that provoked by PDGF or FGF, but had no effect on mitogenesis elicited by the growth factors alone. Whereas LTD4 alone did not augment phosphorylation of extracellular signal-regulated kinase (Erk-1/2 and Akt, it increased phosphorylation of PKC in a Gi-dependent manner. Addition of LTD4 prolonged the duration of EGF-induced phosphorylation of Erk-1/2 and Akt, both of which were sensitive to PTX. The effect of cys-LTs involves a PTX-sensitive and PKC-mediated intracellular pathway leading to sustained growth factor-dependent phosphorylation of Erk-1/2 and Akt.

  13. Spatial cluster analysis of nanoscopically mapped serotonin receptors for classification of fixed brain tissue

    Science.gov (United States)

    Sams, Michael; Silye, Rene; Göhring, Janett; Muresan, Leila; Schilcher, Kurt; Jacak, Jaroslaw

    2014-01-01

    We present a cluster spatial analysis method using nanoscopic dSTORM images to determine changes in protein cluster distributions within brain tissue. Such methods are suitable to investigate human brain tissue and will help to achieve a deeper understanding of brain disease along with aiding drug development. Human brain tissue samples are usually treated postmortem via standard fixation protocols, which are established in clinical laboratories. Therefore, our localization microscopy-based method was adapted to characterize protein density and protein cluster localization in samples fixed using different protocols followed by common fluorescent immunohistochemistry techniques. The localization microscopy allows nanoscopic mapping of serotonin 5-HT1A receptor groups within a two-dimensional image of a brain tissue slice. These nanoscopically mapped proteins can be confined to clusters by applying the proposed statistical spatial analysis. Selected features of such clusters were subsequently used to characterize and classify the tissue. Samples were obtained from different types of patients, fixed with different preparation methods, and finally stored in a human tissue bank. To verify the proposed method, samples of a cryopreserved healthy brain have been compared with epitope-retrieved and paraffin-fixed tissues. Furthermore, samples of healthy brain tissues were compared with data obtained from patients suffering from mental illnesses (e.g., major depressive disorder). Our work demonstrates the applicability of localization microscopy and image analysis methods for comparison and classification of human brain tissues at a nanoscopic level. Furthermore, the presented workflow marks a unique technological advance in the characterization of protein distributions in brain tissue sections.

  14. Characterization and distribution of receptors for the atrial natriuretic peptides in mammalian brain

    International Nuclear Information System (INIS)

    Quirion, R.; Dalpe, M.; Dam, T.V.

    1986-01-01

    Both rat 125 I-labeled atrial natriuretic polypeptide [ 125 I-ANP or atrial natriuretic factor fragment ANF-(99-126)] and human 125 I-α-ANP or human ANF-(99-126)] bind with high specificity and affinity to an apparent single class of sites in guinea pig brain. Similar results have been reported in peripheral tissues, which indicate that central and peripheral ANP binding sites have fairly similar structural requirements. In vitro receptor autoradiography shows that in the guinea pig brain, 125 I-ANP binding sites are highly concentrated in the external plexiform layer of the olfactory bulb, subfornical organ, various thalamic nuclei, medial geniculate nucleus, and cerebellum. Lower densities are found in the central nucleus of the amygdala, dentate gyrus, hippocampus, and area postrema. Most remaining regions contain much lower densities of sites. In rat brain 125 I-ANP binding sites are differentially distributed, with high densities in the subfornical organ, area postrema, and linings of ventricles but low densities in the thalamus and cerebellum. In monkey brain, 125 I-ANP binding sites are concentrated in the cerebellum. The presence of high densities of 125 I-ANP binding sites in various brain regions strongly suggests the existence of a family of brain-heart peptides, in analogy to the well-known brain-gut peptides. Moreover, the extensive distribution of 125 I-ANP binding sites in mammalian brain suggests that the possible roles of ANP/ANF-like peptides in brain are not restricted to the central regulation of cardiovascular parameters

  15. Sigma1 and dopamine D2 receptor occupancy in the mouse brain after a single administration of haloperidol and two dopamine D2-like receptor ligands

    International Nuclear Information System (INIS)

    Ishiwata, Kiichi; Kawamura, Kazunori; Kobayashi, Tadayuki; Matsuno, Kiyoshi

    2003-01-01

    We investigated sigma 1 and dopamine D 2 receptor occupancy in mouse brain after a single injection of haloperidol, nemonapride, or spiperone using [ 11 C]SA4503 and [ 11 C]raclopride, respectively. Co-injection of the three compounds significantly blocked the uptake of each radioligand. Six hours later, only haloperidol blocked [ 11 C]SA4503 uptake, while all three reduced [ 11 C]raclopride uptake. Sigma 1 receptor occupancy by haloperidol was reduced to 19% at day 2 when D 2 receptor occupancy disappeared. [ 11 C]SA4503 would be applicable to the investigation of sigma 1 receptor occupancy of antispychotic drugs using PET

  16. Social information changes stress hormone receptor expression in the songbird brain.

    Science.gov (United States)

    Cornelius, Jamie M; Perreau, Gillian; Bishop, Valerie R; Krause, Jesse S; Smith, Rachael; Hahn, Thomas P; Meddle, Simone L

    2018-01-01

    Social information is used by many vertebrate taxa to inform decision-making, including resource-mediated movements, yet the mechanisms whereby social information is integrated physiologically to affect such decisions remain unknown. Social information is known to influence the physiological response to food reduction in captive songbirds. Red crossbills (Loxia curvirostra) that were food reduced for several days showed significant elevations in circulating corticosterone (a "stress" hormone often responsive to food limitation) only if their neighbors were similarly food restricted. Physiological responses to glucocorticoid hormones are enacted through two receptors that may be expressed differentially in target tissues. Therefore, we investigated the influence of social information on the expression of the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA in captive red crossbill brains. Although the role of MR and GR in the response to social information may be highly complex, we specifically predicted social information from food-restricted individuals would reduce MR and GR expression in two brain regions known to regulate hypothalamic-pituitary-adrenal (HPA) activity - given that reduced receptor expression may lessen the efficacy of negative feedback and release inhibitory tone on the HPA. Our results support these predictions - offering one potential mechanism whereby social cues could increase or sustain HPA-activity during stress. The data further suggest different mechanisms by which metabolic stress versus social information influence HPA activity and behavioral outcomes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Effects of isomers of apomorphines on dopamine receptors in striatal and limbic tissue of rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Kula, N.S.; Baldessarini, R.J.; Bromley, S.; Neumeyer, J.L.

    1985-09-16

    The optical isomers of apomorphine (APO) and N-propylnorapomorphine (NPA) were interacted with three biochemical indices of dopamine (Da) receptors in extrapyramidal and limbic preparations of rat brain tissues. There were consistent isomeric preferences for the R(-) configuration of both DA analogs in stimulation adenylate cyclase (D-1 sites) and in competing for high affinity binding of /sup 3/H-spiroperidol (D-2 sites) and of /sup 3/H-ADTN (DA agonist binding sites) in striatal tissue, with lesser isomeric differences in the limbic tissue. The S(+) apomorphines did not inhibit stimulation of adenylate cyclase by DA. The tendency for greater activity of higher apparent affinity of R(-) apomorphines in striatum may reflect the evidently greater abundance of receptor sites in that region. There were only small regional differences in interactions of the apomorphine isomers with all three receptor sites, except for a strong preference of (-)NPA for striatal D-2 sites. These results do not parallel our recent observations indicating potent and selective antidopaminergic actions of S(+) apomorphines in the rat limbic system. They suggest caution in assuming close parallels between current biochemical functional, especially behavioral, methods of evaluating dopamine receptors of mammalian brain.

  18. Nicotinic cholinergic receptor in brain detected by binding of. cap alpha. -(/sup 3/H)bungarotoxin

    Energy Technology Data Exchange (ETDEWEB)

    Eterovic, V A; Bennett, E L

    1974-01-01

    ..cap alpha..-(/sup 3/H)bungarotoxin was prepared by catalytic reduction of iodinated ..cap alpha..-bungarotoxin with tritium gas. Crude mitochondrial fraction from rat cerebral cortex bound 40 x 10/sup -15/ to 60 x 10/sup -15/ moles of ..cap alpha..-(/sup 3/H)bungarotoxin per mg of protein. This binding was reduced by 50% in the presence of approx. 10/sup -6/ M d-tubocurarine or nicotine, 10/sup -5/ M acetylcholine, 10/sup -4/ M carbamylcholine or decamethonium or 10/sup -3/ M atropine. Hexamethonium and eserine were the least effective of the drugs tested. Crude mitochondrial fraction was separated into myelin, nerve endings, and mitochondria. The highest binding of toxin per mg of protein was found in nerve endings, as well as the greatest inhibition of toxin binding by d-tubocurarine. Binding of ..cap alpha..-(/sup 3/H)bungarotoxin to membranes obtained by osmotic shock of the crude mitochondrial fraction indicates that the receptor for the toxin is membrane bound. /sup 125/I-labeled ..cap alpha..-bungarotoxin, prepared with Na/sup 125/I and chloramine T, was highly specific for the acetylcholine receptor in diaphragm, however, it was less specific and less reliable than ..cap alpha..-(/sup 3/H)bungarotoxin in brain. It is concluded that a nicotinic cholinergic receptor exists in brain, and that ..cap alpha..-(/sup 3/H)bungarotoxin is a suitable probe for this receptor.

  19. Radioligands for brain 5-HT{sub 2} receptor imaging in vivo: why do we need them?

    Energy Technology Data Exchange (ETDEWEB)

    Busatto, G.F. [Section of Clinical Neuropharmacology, Dept. of Psychological Medicine, Inst. of Psychiatry, London (United Kingdom)

    1996-08-01

    Recently, PET and SPET radiotracers with high specificity for 5-HT{sub 2} receptors have been developed. These have been studied in baboons and humans with promising results, displaying a binding profile compatible with the brain distribution of 5-HT{sub 2} receptors. It is predicted that studies with the newly developed 5-HT radioligands will substantially increase knowledge about the pharmacology of brain disorders. (orig./MG)

  20. Identification of endogenous opioid receptor components in rat brain using a monoclonal antibody

    Energy Technology Data Exchange (ETDEWEB)

    Bero, L.A.; Roy, S.; Lee, N.M.

    1988-11-01

    A monoclonal antibody generated against the tertiary structure of a partially purified opioid binding protein was used to probe the structure of the dynorphin and beta-endorphin receptors. The Fab fragment 3B4F11 inhibited completely the binding of 125I-beta-endorphin and (3H)dynorphin to rat brain P2 membranes with IC50 values of 26 ng/ml and 40 ng/ml, respectively. To explore further the interaction of 3B4F11 with the beta-endorphin receptor, the effect of the Fab fragment on 125I-beta-endorphin cross-linking to rat brain membranes was examined. 125I-beta-endorphin was covalently bound to three major species of approximate molecular weights 108,000, 73,000, and 49,000. The delta-selective ligand D-Pen2, D-pen5enkephalin was least effective at inhibiting the cross-linking of beta-endorphin, whereas the micro-selective ligand Tyr-D-Ala-Gly-NMe-Phe-Gly-ol and kappa-selective ligand U50488 inhibited beta-endorphin cross-linking to the 108,000 and 73,000 Da species. Both 3B4F11 and beta-endorphin prevented the covalent binding of 125I-beta-endorphin to all three labeled species. These findings suggest that micro and kappa receptor types might have some structural similarities, whereas the delta receptor type might differ in molecular size. In addition, the micro, kappa, and delta ligands might have different primary sequences, whereas their tertiary structures might share regions of molecular homology with all three receptor constituents labeled by 125I-beta-endorphin. 3B4F11 will be a valuable tool for the purification and isolation of the several components of the beta-endorphin receptor complex.

  1. Nuclear receptor TLX regulates cell cycle progression in neural stem cells of the developing brain.

    Science.gov (United States)

    Li, Wenwu; Sun, Guoqiang; Yang, Su; Qu, Qiuhao; Nakashima, Kinichi; Shi, Yanhong

    2008-01-01

    TLX is an orphan nuclear receptor that is expressed exclusively in vertebrate forebrains. Although TLX is known to be expressed in embryonic brains, the mechanism by which it influences neural development remains largely unknown. We show here that TLX is expressed specifically in periventricular neural stem cells in embryonic brains. Significant thinning of neocortex was observed in embryonic d 14.5 TLX-null brains with reduced nestin labeling and decreased cell proliferation in the germinal zone. Cell cycle analysis revealed both prolonged cell cycles and increased cell cycle exit in TLX-null embryonic brains. Increased expression of a cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin D1 provide a molecular basis for the deficiency of cell cycle progression in embryonic brains of TLX-null mice. Furthermore, transient knockdown of TLX by in utero electroporation led to precocious cell cycle exit and differentiation of neural stem cells followed by outward migration. Together these results indicate that TLX plays an important role in neural development by regulating cell cycle progression and exit of neural stem cells in the developing brain.

  2. Ontogeny of phorbol ester receptors in rat brain studied by in vitro autoradiography

    International Nuclear Information System (INIS)

    Miyoshi, R.; Kito, S.

    1990-01-01

    The ontogeny of phorbol ester receptors, which have been considered to correspond to protein kinase C, in the rat brain was studied through in vitro autoradiography with 3 H-phorbol 12,13-dibutyrate ( 3 H-PDBu). The distribution of 3 H-PDBu binding sites in the adult rat brain was similar to the previous reports by other researchers. The developmental pattern of 3 H-PDBu binding sites varried with brain region. 3 H-PDBu binding sites in the amygdala, thalamus, stratum pyramidale of CA 1 of the hippocampus, dentate gyrus, superior colliculus, substantia nigra, interpeduncular nucleus and cerebellar molecular layer were postnatally increased to adult levels and after that they remained constant. On the other hand, in the stratum oriens and stratum radiatum of CA 1 of the hippocampus, and in the lateral and medial geniculate bodies, 3 H-PDBu binding sites reached peaks at 21 or 28 days of postnatal age and after that they declined to adult levels. The cerebellar granular layer showed a low level of 3 H-PDBu binding sites throughout all the ontogenetic stages. A distinct ontogenetic pattern of phorbol ester receptors in various regions of the brain may reflect a role of protein kinase C in the neural development of each discrete area. (Authors)

  3. Insulin and insulin-like growth factor receptors in the brain: physiological and pathological aspects.

    Science.gov (United States)

    Werner, Haim; LeRoith, Derek

    2014-12-01

    The involvement of insulin, the insulin-like growth factors (IGF1, IGF2) and their receptors in central nervous system development and function has been the focus of scientific interest for more than 30 years. The insulin-like peptides, both locally-produced proteins as well as those transported from the circulation into the brain via the blood-brain barrier, are involved in a myriad of biological activities. These actions include, among others, neuronal survival, neurogenes, angiogenesis, excitatory and inhibitory neurotransmission, regulation of food intake, and cognition. In recent years, a linkage between brain insulin/IGF1 and certain neuropathologies has been identified. Epidemiological studies have demonstrated a correlation between diabetes (mainly type 2) and Alzheimer׳s disease. In addition, an aberrant decline in IGF1 values was suggested to play a role in the development of Alzheimer׳s disease. The present review focuses on the expression and function of insulin, IGFs and their receptors in the brain in physiological and pathological conditions. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  4. Implications of astrocytes in mediating the protective effects of Selective Estrogen Receptor Modulators upon brain damage

    Directory of Open Access Journals (Sweden)

    George E. Barreto

    2015-04-01

    Full Text Available Selective Estrogen Receptor Modulators (SERMs are steroidal or non-steroidal compounds that are already used in clinical practice for the treatment of breast cancer, osteoporosis and menopausal symptoms. While SERMs actions in the breast, bone, and uterus have been well characterized, their actions in the brain are less well understood. Previous works have demonstrated the beneficial effects of SERMs in different chronic neurodegenerative diseases like Alzheimer, Parkinson’s disease and Multiple sclerosis, as well as acute degeneration as stroke and traumatic brain injury. Moreover, these compounds exhibit similar protective actions as those of estradiol in the Central Nervous System, overt any secondary effect. For these reasons, in the past few years, there has been a growing interest in the neuroprotective effects exerted directly or indirectly by SERMs in the SNC. In this context, astrocytes play an important role in the maintenance of brain metabolism, and antioxidant support to neurons, thus indicating that better protection of astrocytes are an important asset targeting neuronal protection. Moreover, various clinical and experimental studies have reported that astrocytes are essential for the neuroprotective effects of SERMs during neuronal injuries, as these cells express different estrogen receptors in cell membrane, demonstrating that part of SERMs effects upon injury may be mediated by astrocytes. The present work highlights the current evidence on the protective mechanisms of SERMs, such as tamoxifen and raloxifene, in the SNC, and their modulation of astrocytic properties as promising therapeutic targets during brain damage.

  5. Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse

    Science.gov (United States)

    Pellegrino, Rosa Maria; Boda, Enrica; Montarolo, Francesca; Boero, Martina; Mezzanotte, Mariarosa; Saglio, Giuseppe; Buffo, Annalisa; Roetto, Antonella

    2016-01-01

    The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc response. Moreover, Tfr2-KO mice presented a selective overactivation of neurons in the limbic circuit and the emergence of an anxious-like behaviour. Furthermore, microglial cells showed a particular sensitivity to iron perturbation. We conclude that Tfr2 is a key regulator of brain iron homeostasis and propose a role for Tfr2 alpha in the regulation of anxiety circuits. PMID:27477597

  6. Screening of Toll-like receptors expression in multiple system atrophy brains

    DEFF Research Database (Denmark)

    Brudek, Tomasz; Winge, Kristian; Agander, Tina Klitmøller

    2013-01-01

    The family of Toll-like receptors (TLRs) plays a key role in controlling innate immune responses to a wide variety of pathogen-associated molecules. It was recently suggested that TLRs have an important role in the crosstalk between neurons and glial cells in the central nervous system, thus...... inclusions in oligodendrocytes. α-Synuclein can act as a danger-associated molecular pattern and alter TLR expression thereby activating inflammatory responses in the brain. In this study, using real-time PCR, we assessed the expression of TLRs (TLR1-10) in selected areas of MSA brains (substantia nigra......TLR-1 mRNA were elevated in substantia nigra and striatum whereas levels of hTLR-8 and hTLR-9 mRNAs were significantly higher in cerebella from MSA patients. The concerted alteration of expression of multiple TLRs in MSA brains can be of relevance for understanding the pathogenesis of the disease....

  7. Neuroanatomical patterns of the mu, delta, and kappa opioid receptors of rat brain as determined by quantitative in vitro autoradiography

    International Nuclear Information System (INIS)

    Tempel, A.; Zukin, R.S.

    1987-01-01

    Highly specific radioligands and quantitative autoradiography reveal strikingly different neuroanatomical patterns for the mu, delta, and kappa opioid receptors of rat brain. The mu receptors are most densely localized in patches in the striatum, layers I and III of the cortex, the pyramidal cell layer of the hippocampal formation, specific nuclei of the thalamus, the pars reticulata of the substantia nigra, the interpeduncular nucleus, and the locus coeruleus. In contrast, delta receptors are highly confined, exhibiting selective localization in layers I, II, and VIa of the neocortex, a diffuse pattern in the striatum, and moderate concentration in the pars reticulata of the substantia nigra and in the interpeduncular nucleus. delta receptors are absent in most other brain structures. This distribution is unexpected in that the enkephalins, the putative endogenous ligands of the delta receptor, occur essentially throughout the brain. The kappa receptors of rat brain exhibit a third pattern distinct from that of the mu and delta receptors. kappa receptors occur at low density in patches in the striatum and at particularly high density in the nucleus accumbens, along the pyramidal and molecular layers of the hippocampus, in the granular cell layer of the dentate gyrus, specific midline nuclei of the thalamus, and hindbrain regions. kappa receptors appear to be uniformly distributed across regions in the neocortex with the exception of layer III, which revealed only trace levels of binding. An important conclusion of the present study is that delta receptors occur at high density only in the forebrain and in two midbrain structures, whereas mu and kappa receptors exhibit discrete patterns in most major brain regions

  8. Development of gamma emitting receptor-binding radiotracers for imaging the brain and pancreas. Progress report, February 1983-September 1984

    International Nuclear Information System (INIS)

    Reba, R.C.

    1984-01-01

    The possibility of measuring the change in receptor concentration as a function of disease by external imaging was investigated. The structure-binding-relationship which provides optimal localization of radiolabelled antagonist of the muscarinic acetylcholine receptors in the brain was studied. These relationships were also studied with respect to localization in the pancreas

  9. Association between dopamine D4 receptor polymorphism and age related changes in brain glucose metabolism.

    Directory of Open Access Journals (Sweden)

    Nora D Volkow

    Full Text Available Aging is associated with reductions in brain glucose metabolism in some cortical and subcortical regions, but the rate of decrease varies significantly between individuals, likely reflecting genetic and environmental factors and their interactions. Here we test the hypothesis that the variant of the dopamine receptor D4 (DRD4 gene (VNTR in exon 3, which has been associated with novelty seeking and sensitivity to environmental stimuli (negative and positive including the beneficial effects of physical activity on longevity, influence the effects of aging on the human brain. We used positron emission tomography (PET and [(18F]fluoro-D-glucose ((18FDG to measure brain glucose metabolism (marker of brain function under baseline conditions (no stimulation in 82 healthy individuals (age range 22-55 years. We determined their DRD4 genotype and found an interaction with age: individuals who did not carry the 7-repeat allele (7R-, n = 53 had a significant (p<0.0001 negative association between age and relative glucose metabolism (normalized to whole brain glucose metabolism in frontal (r = -0.52, temporal (r = -0.51 and striatal regions (r = -0.47, p<0.001; such that older individuals had lower metabolism than younger ones. In contrast, for carriers of the 7R allele (7R+ n = 29, these correlations with age were not significant and they only showed a positive association with cerebellar glucose metabolism (r = +0.55; p = 0.002. Regression slopes of regional brain glucose metabolism with age differed significantly between the 7R+ and 7R- groups in cerebellum, inferior temporal cortex and striatum. These results provide evidence that the DRD4 genotype might modulate the associations between regional brain glucose metabolism and age and that the carriers of the 7R allele appear to be less sensitive to the effects of age on brain glucose metabolism.

  10. The brain cytoplasmic RNA BC1 regulates dopamine D-2 receptor-mediated transmission in the striatum

    OpenAIRE

    Centonze, Diego; Rossi, Silvia; Napoli, Ilaria; Mercaldo, Valentina; Lacoux, Caroline; Ferrari, Francesca; Ciotti, Maria Teresa; De Chiara, Valentina; Prosperetti, Chiara; Maccarrone, Mauro; Fezza, Filomena; Calabresi, Paolo; Bernardi, Giorgio; Bagni, Claudia

    2007-01-01

    Dopamine D-2 receptor (D2DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor-associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D-2 receptors in this brain area are essentially obscure. We have studied the physiological responses of the D2DR stimulations in mice...

  11. Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin

    International Nuclear Information System (INIS)

    Lesniak, M.A.; Hill, J.M.; Kiess, W.; Rojeski, M.; Pert, C.B.; Roth, J.

    1988-01-01

    Receptors for insulin-like growth factor I (IGF-I) in rat brain were visualized using autoradiography with [125I]IGF-I. The binding of the labeled peptide was competed for fully by high concentrations of unlabeled IGF-I. At intermediate concentrations of unlabeled peptide the binding of [125I]IGF-I was competed for by unlabeled IGF-I more effectively than by IGF-II or insulin, which is typical of receptors for IGF-I. Essentially every brain section shows specific binding of IGF-I, and the pattern of binding of IGF-I to its receptors correlated well with the cytoarchitectonic structures. In parallel studies we showed that [125I]IGF-II was bound to tissue sections of rat brain and that the binding was competed for by an excess of unlabeled IGF-II. However, intermediate concentrations of unlabeled peptides gave inconclusive results. To confirm that the binding of [125I]IGF-II was to IGF-II receptors, we showed that antibodies specific for the IGF-II receptor inhibited the binding of labeled IGF-II. Furthermore, the binding of the antibody to regions of the brain section, visualized by the application of [125I]protein-A, gave patterns indistinguishable from those obtained with [125I]IGF-II alone. Again, the binding was very widely distributed throughout the central nervous system, and the patterns of distribution corresponded well to the underlying neural structures. Densitometric analysis of the receptors enabled us to compare the distribution of IGF-I receptors with that of IGF-II receptors as well as retrospectively with that of insulin receptors

  12. In vivo imaging of brain androgen receptors in rats: a [18F]FDHT PET study

    International Nuclear Information System (INIS)

    Khayum, M.A.; Doorduin, J.; Antunes, I.F.; Kwizera, C.; Zijlma, R.; Boer, J.A. den; Dierckx, R.A.J.O.; Vries, E.F.J. de

    2015-01-01

    Introduction: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16β-[ 18 F]fluoro-5α-dihydrotestosterone ([ 18 F]FDHT) to image AR expression in the brain. Methods: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [ 18 F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1 mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution. Results: PET imaging and ex vivo biodistribution studies showed low [ 18 F]FDHT uptake in all brain regions, except pituitary. [ 18 F]FDHT uptake in the surrounding cranial bones was high and increased over time. [ 18 F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [ 18 F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone. Conclusion: The results of this study indicate that imaging of AR availability in rat brain with [ 18 F]FDHT PET is not feasible. The low AR expression in the brain, the

  13. {beta}-adrenergic receptor density and adenylate cyclase activity in lead-exposed rat brain after cessation of lead exposure

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Huoy-Rou [I-Shou University, Department of Biomedical Engineering, Dashu Shiang, Kaohsiung County (Taiwan); Tsao, Der-An [Fooyin University of Technology, Department of Medical Technology (Taiwan); Yu, Hsin-Su [Taiwan University, Department of Dermatology, College of Medicine (Taiwan); Ho, Chi-Kung [Kaohsiung Medical University, Occupational Medicine (Taiwan); Kaohsiung Medical University, Graduate Institute of Medicine, Research Center for Occupational Disease (Taiwan)

    2005-01-01

    To understanding the reversible or irreversible harm to the {beta}-adrenergic system in the brain of lead-exposed rats, this study sets up an animal model to estimate the change in the sympathetic nervous system of brain after lead exposure was withdrawn. We address the following topics in this study: (a) the relationship between withdrawal time of lead exposure and brain {beta}-adrenergic receptor, blood lead level, and brain lead level in lead-exposed rats after lead exposure was stopped; and (b) the relationship between lead level and {beta}-adrenergic receptor and cyclic AMP (c-AMP) in brain. Wistar rats were chronically fed with 2% lead acetate and water for 2 months. Radioligand binding was assayed by a method that fulfilled strict criteria of {beta}-adrenergic receptor using the ligand [{sup 125}I]iodocyanopindolol. The levels of lead were determined by electrothermal atomic absorption spectrometry. The c-AMP level was determined by radioimmunoassay. The results showed a close relationship between decreasing lead levels and increasing numbers of brain {beta}-adrenergic receptors and brain adenylate cyclase activity after lead exposure was withdrawn. The effect of lead exposure on the {beta}-adrenergic system of the brain is a partly reversible condition. (orig.)

  14. Interleukin-1 Receptor in Seizure Susceptibility after Traumatic Injury to the Pediatric Brain.

    Science.gov (United States)

    Semple, Bridgette D; O'Brien, Terence J; Gimlin, Kayleen; Wright, David K; Kim, Shi Eun; Casillas-Espinosa, Pablo M; Webster, Kyria M; Petrou, Steven; Noble-Haeusslein, Linda J

    2017-08-16

    Epilepsy after pediatric traumatic brain injury (TBI) is associated with poor quality of life. This study aimed to characterize post-traumatic epilepsy in a mouse model of pediatric brain injury, and to evaluate the role of interleukin-1 (IL-1) signaling as a target for pharmacological intervention. Male mice received a controlled cortical impact or sham surgery at postnatal day 21, approximating a toddler-aged child. Mice were treated acutely with an IL-1 receptor antagonist (IL-1Ra; 100 mg/kg, s.c.) or vehicle. Spontaneous and evoked seizures were evaluated from video-EEG recordings. Behavioral assays tested for functional outcomes, postmortem analyses assessed neuropathology, and brain atrophy was detected by ex vivo magnetic resonance imaging. At 2 weeks and 3 months post-injury, TBI mice showed an elevated seizure response to the convulsant pentylenetetrazol compared with sham mice, associated with abnormal hippocampal mossy fiber sprouting. A robust increase in IL-1β and IL-1 receptor were detected after TBI. IL-1Ra treatment reduced seizure susceptibility 2 weeks after TBI compared with vehicle, and a reduction in hippocampal astrogliosis. In a chronic study, IL-1Ra-TBI mice showed improved spatial memory at 4 months post-injury. At 5 months, most TBI mice exhibited spontaneous seizures during a 7 d video-EEG recording period. At 6 months, IL-1Ra-TBI mice had fewer evoked seizures compared with vehicle controls, coinciding with greater preservation of cortical tissue. Findings demonstrate this model's utility to delineate mechanisms underlying epileptogenesis after pediatric brain injury, and provide evidence of IL-1 signaling as a mediator of post-traumatic astrogliosis and seizure susceptibility. SIGNIFICANCE STATEMENT Epilepsy is a common cause of morbidity after traumatic brain injury in early childhood. However, a limited understanding of how epilepsy develops, particularly in the immature brain, likely contributes to the lack of efficacious treatments

  15. Apo-ghrelin receptor (apo-GHSR1a Regulates Dopamine Signaling in the Brain

    Directory of Open Access Journals (Sweden)

    Andras eKern

    2014-08-01

    Full Text Available The orexigenic peptide hormone ghrelin is synthesized in the stomach and its receptor growth hormone secretagogue receptor (GHSR1a is expressed mainly in the central nervous system (CNS. In this review we confine our discussion to the physiological role of GHSR1a in the brain. Paradoxically, despite broad expression of GHSR1a in the CNS, other than trace amounts in the hypothalamus, ghrelin is undetectable in the brain. In our efforts to elucidate the function of the ligand-free ghrelin receptor (apo-GHSR1a we identified subsets of neurons that co-express GHSR1a and dopamine receptors. In this review we focus on interactions between apo-GHSR1a and dopamine-2 receptor (DRD2 and formation of GHSR1a:DRD2 heteromers in hypothalamic neurons that regulate appetite, and discuss implications for the treatment of Prader-Willi syndrome. GHSR1a antagonists of distinct chemical structures, a quinazolinone and a triazole, respectively enhance and inhibit dopamine signaling through GHSR1a:DRD2 heteromers by an allosteric mechanism. This finding illustrates a potential strategy for designing the next generation of drugs for treating eating disorders as well as psychiatric disorders caused by abnormal dopamine signaling. Treatment with a GHSR1a antagonist that enhances dopamine/DRD2 activity in GHSR1a:DRD2 expressing hypothalamic neurons has the potential to inhibit the uncontrollable hyperphagia associated with Prader-Willi syndrome. DRD2 antagonists are prescribed for treating schizophrenia, but these block dopamine signaling in all DRD2 expressing neurons and are associated with adverse side effects, including enhanced appetite and excessive weight gain. A GHSR1a antagonist of structural class that allosterically blocks dopamine/DRD2 action in GHSR1a:DRD2 expressing neurons would have no effect on neurons expressing DRD2 alone; therefore, the side effects of DRD2 antagonists would potentially be reduced thereby enhancing patient compliance.

  16. (/sup 3/H)Haloperidol labels brain dopamine receptors after its injection into the internal carotid artery of the rat

    Energy Technology Data Exchange (ETDEWEB)

    D' Ambrosio, A; Zivkovic, B; Bartholini, G [Research Department, Synthelabo-L.E.R.S., Paris (France)

    1982-04-29

    Pulse injection of (/sup 3/H)haloperidol (0.1 ..mu..Ci; 0.003 ..mu..g) into the internal carotid artery of the rat specifically labelled dopamine receptors in striatum and olfactory tubercle, as indicated by the kinetics of, and the effects of neuroleptic drugs on, the ligand disposition. The described method may prove useful for labelling brain receptors with ligands which readily cross the blood-brain barrier but which do not selectively mark their receptors if injected systemically.

  17. [3H]Haloperidol labels brain dopamine receptors after its injection into the internal carotid artery of the rat

    International Nuclear Information System (INIS)

    D'Ambrosio, A.; Zivkovic, B.; Bartholini, G.

    1982-01-01

    Pulse injection of [ 3 H]haloperidol (0.1 μCi; 0.003 μg) into the internal carotid artery of the rat specifically labelled dopamine receptors in striatum and olfactory tubercle, as indicated by the kinetics of, and the effects of neuroleptic drugs on, the ligand disposition. The described method may prove useful for labelling brain receptors with ligands which readily cross the blood-brain barrier but which do not selectively mark their receptors if injected systemically. (Auth.)

  18. Brain metastasis in human epidermal growth factor receptor 2-positive breast cancer: from biology to treatment

    Energy Technology Data Exchange (ETDEWEB)

    Koo, Tae Ryool [Dept. of Radiation Oncology, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon (Korea, Republic of); Kim, In Ah [Dept. of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam (Korea, Republic of)

    2016-03-15

    Overexpression of human epidermal growth factor receptor 2 (HER2) is found in about 20% of breast cancer patients. With treatment using trastuzumab, an anti-HER2 monoclonal antibody, systemic control is improved. Nonetheless, the incidence of brain metastasis does not be improved, rather seems to be increased in HER2-positive breast cancer. The mainstay treatment for brain metastases is radiotherapy. According to the number of metastatic lesions and performance status of patients, radiosurgery or whole brain radiotherapy can be performed. The concurrent use of a radiosensitizer further improves intracranial control. Due to its large molecular weight, trastuzumab has a limited ability to cross the blood-brain barrier. However, small tyrosine kinase inhibitors such as lapatinib, has been noted to be a promising agent that can be used as a radiosensitizer to affect HER2-positive breast cancer. This review will outline general management of brain metastases and will focus on preclinical findings regarding the radiosensitizing effect of small molecule HER2 targeting agents.

  19. Adenosine A1 receptors contribute to immune regulation after neonatal hypoxic ischemic brain injury.

    Science.gov (United States)

    Winerdal, Max; Winerdal, Malin E; Wang, Ying-Qing; Fredholm, Bertil B; Winqvist, Ola; Ådén, Ulrika

    2016-03-01

    Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A1 receptor deficiency (A1R(-/-)) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction size evaluated. Flow cytometry was performed on brain-infiltrating cells, and semi-automated analysis of flow cytometric data was applied. A1R(-/-) mice displayed larger infarctions (+33%, p beam walking tests (44% more mistakes, p < 0.05) than wild-type (WT) mice. Myeloid cell activation after injury was enhanced in A1R(-/-) versus WT brains. Activated B lymphocytes expressing IL-10 infiltrated the brain after HI in WT, but were less activated and did not increase in relative frequency in A1R(-/-). Also, A1R(-/-) B lymphocytes expressed less IL-10 than their WT counterparts, the A1R antagonist DPCPX decreased IL-10 expression whereas the A1R agonist CPA increased it. CD4(+) T lymphocytes including FoxP3(+) T regulatory cells, were unaffected by genotype, whereas CD8(+) T lymphocyte responses were smaller in A1R(-/-) mice. Using PCA to characterize the immune profile, we could discriminate the A1R(-/-) and WT genotypes as well as sham operated from HI-subjected animals. We conclude that A1R signaling modulates IL-10 expression by immune cells, influences the activation of these cells in vivo, and affects outcome after HI.

  20. Receptor-mediated transcytosis of cyclophilin B through the blood-brain barrier.

    Science.gov (United States)

    Carpentier, M; Descamps, L; Allain, F; Denys, A; Durieux, S; Fenart, L; Kieda, C; Cecchelli, R; Spik, G

    1999-07-01

    Cyclophilin B (CyPB) is a cyclosporin A (CsA)-binding protein mainly located in intracellular vesicles and secreted in biological fluids. In previous works, we demonstrated that CyPB interacts with T lymphocytes and enhances in vitro cellular incorporation and activity of CsA. In addition to its immunosuppressive activity, CsA is able to promote regeneration of damaged peripheral nerves. However, the crossing of the drug from plasma to neural tissue is restricted by the relative impermeability of the blood-brain barrier. To know whether CyPB might also participate in the delivery of CsA into the brain, we have analyzed the interactions of CyPB with brain capillary endothelial cells. First, we demonstrated that CyPB binds to two types of binding sites present at the surface of capillary endothelial cells from various species of tissues. The first type of binding sites (K(D) = 300 nM; number of sites = 3 x 10(6)) is related to interactions with negatively charged compounds such as proteoglycans. The second type of binding sites, approximately 50,000 per cell, exhibits a higher affinity for CyPB (K(D) = 15 nM) and is involved in an endocytosis process, indicating it might correspond to a functional receptor. Finally, the use of an in vitro model of blood-brain barrier allowed us to demonstrate that CyPB is transcytosed by a receptor-mediated pathway (flux = 16.5 fmol/cm2/h). In these conditions, CyPB did not significantly modify the passage of CsA, indicating that it is unlikely to provide a pathway for CsA brain delivery.

  1. Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects.

    Directory of Open Access Journals (Sweden)

    Emmanuel S Onaivi

    Full Text Available BACKGROUND: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R but not (H316Y polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.

  2. Autoradiographic localization of nicotinic acetylcholine receptors in the brain of the zebra finch (Poephila guttata)

    International Nuclear Information System (INIS)

    Watson, J.T.; Adkins-Regan, E.; Whiting, P.; Lindstrom, J.M.; Podleski, T.R.

    1988-01-01

    We have localized nicotinic acetylcholine receptors in the zebra finch brain by using three 125I-labelled ligands: alpha bungarotoxin and two monoclonal antibodies to neuronal nicotinic receptors. Unfixed brains from intact adult male and female zebra finches were prepared for in vitro autoradiography. Low-resolution film autoradiograms and high-resolution emulsion autoradiograms were prepared for each of the three ligands. The major brain structures that bind all three of the ligands are hippocampus; hyperstriatum dorsalis; hyperstriatum ventralis; nucleus lentiformis mesencephali; nucleus pretectalis, some layers of the optic tectum; nucleus mesencephalicus lateralis; pars dorsalis; locus ceruleus; and all cranial motor nuclei except nucleus nervi hypoglossi. The major structures labelled only by [125I]-alpha bungarotoxin binding included hyperstriatum accessorium and the nuclei: preopticus medialis, medialis hypothalami posterioris, semilunaris, olivarius inferior, and the periventricular organ. Of the song control nuclei, nucleus magnocellularis of the anterior neostriatum; hyperstriatum ventralis, pars caudalis; nucleus intercollicularis; and nucleus hypoglossus were labelled. The binding patterns of the two antibodies were similar to one another but not identical. Both labelled nucleus spiriformis lateralis and nucleus geniculatus lateralis, pars ventralis especially heavily and also labelled the nucleus habenula medialis; nucleus subpretectalis; nucleus isthmi, pars magnocellularis; nucleus reticularis gigantocellularis; nucleus reticularis lateralis; nucleus tractus solitarii; nucleus vestibularis dorsolateralis; nucleus vestibularis lateralis; nucleus descendens nervi trigemini; and the deep cerebellar nuclei

  3. Pharmacological characterization and autoradiographic localization of substance P receptors in guinea pig brain

    International Nuclear Information System (INIS)

    Dam, T.V.; Quirion, R.

    1986-01-01

    [ 3 H]Substance P ([ 3 H]SP) was used to characterize substance P (SP) receptor binding sites in guinea pig brain using membrane preparations and in vitro receptor autoradiography. Curvilinear Scatchard analysis shows that [ 3 H]SP binds to a high affinity site (Kd = 0.5 nM) with a Bmax of 16.4 fmol/mg protein and a low affinity site (Kd = 29.6 nM) with a Bmax of 189.1 fmol/mg protein. Monovalent cations generally inhibit [ 3 H]SP binding while divalent cations substantially increased it. The ligand selectivity pattern is generally similar to the one observed in rat brain membrane preparation with SP being more potent than SP fragments and other tachykinins. However, the potency of various nucleotides is different with GMP-PNP greater than GDP greater than GTP. The autoradiographic distribution of [ 3 H]SP binding sites shows that high amounts of sites are present in the hippocampus, striatum, olfactory bulb, central nucleus of the amygdala, certain thalamic nuclei and superior colliculus. The cortex is moderately enriched in [ 3 H]SP binding sites while the substantia nigra contains only very low amounts of sites. Thus, the autoradiographic distribution of SP binding sites is fairly similar in both rat and guinea pig brain

  4. Characterization and localization of arginine vasotocin receptors in the brain and kidney of an amphibian

    International Nuclear Information System (INIS)

    Boyd, S.K.

    1987-01-01

    Because arginine vasotocin (AVT) activates male sexual behaviors in the rough-skinned newt (Taricha granulosa), quantitative autoradiography with radiolabeled arginine vasopressin ( 3 H-AVP) was used to localize and characterize putative AVT receptors in the brain of this amphibian. Binding of 3 H-AVP to sites within the medial pallium was saturable, specific, reversible, of high affinity and low capacity. These binding sites appear to represent authentic central nervous system receptors for AVT. Furthermore, ligand specificity for the binding sites in this amphibian differs from that reported for AVP binding sites in rat brains. Dense concentrations of specific binding sites were located in the olfactory nerve as it entered the olfactory bulb within the medial pallium, dorsal pallium, and amygdala pars lateralis of the telencephalon, and in the tegmental region of the medulla. Concentrations of binding sites differed significantly among various brain regions. A comparison of male and female newts collected during the breeding season revealed no sexual dimorphism. These areas may represent site(s) of action where AVT elicits sexual behaviors in male T. granulosa

  5. Mapping adenosine A1 receptors in the cat brain by positron emission tomography with [11C]MPDX

    International Nuclear Information System (INIS)

    Shimada, Yuhei; Ishiwata, Kiichi; Kiyosawa, Motohiro; Nariai, Tadashi; Oda, Keiichi; Toyama, Hinako; Suzuki, Fumio; Ono, Kenichirou; Senda, Michio

    2002-01-01

    We evaluated the potential of [ 11 C]MPDX as a radioligand for mapping adenosine A 1 receptors in comparison with previously proposed [ 11 C]KF15372 in cat brain by PET. Two tracers showed the same brain distribution. Brain uptake of [ 11 C]MPDX (Ki=4.2 nM) was much higher and washed out faster than that of [ 11 C]KF15372 (Ki=3.0 nM), and was blocked by carrier-loading or displaced with an A 1 antagonist. The regional A 1 receptor distribution evaluated with kinetic analysis is consistent with that previously measured in vitro. [ 11 C]MPDX PET has a potential for mapping adenosine A 1 receptors in brain

  6. Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT{sub 4} receptors with SPET

    Energy Technology Data Exchange (ETDEWEB)

    Pike, Victor W. [MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, W12 0NN, London (United Kingdom); PET Radiopharmaceutical Sciences Section, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, MD 20892-1003, Bethesda (United States); Halldin, Christer; Nobuhara, Kenji; Swahn, Carl-Gunnar; Karlsson, Per; Olsson, Hans; Larsson, Stig; Schnell, Per-Olof; Farde, Lars [Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska Hospital, 17176, Stockholm (Sweden); Hiltunen, Julka [MAP Medical Technologies, Oy, Tikkakoski (Finland); Mulligan, Rachel S. [MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, W12 0NN, London (United Kingdom); Institute of Psychiatry, SE 8AF, De Crespigny Park, Denmark Hill, London (United Kingdom); Centre for PET, Austin and Repatriation Medical Centre, Studley Road, Melbourne VIC 3084 (Australia); Hume, Susan P.; Hirani, Ella [MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, W12 0NN, London (United Kingdom); Imaging Research Solutions Ltd., Cyclotron Building, Hammersmith Hospital, Ducane Road, W12 0NN, London (United Kingdom); Whalley, Jaqueline [MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, W12 0NN, London (United Kingdom); Pilowsky, Lyn S. [Institute of Psychiatry, SE 8AF, De Crespigny Park, Denmark Hill, London (United Kingdom); Institute of Nuclear Medicine, Royal Free and University College, Medical School, Mortimer Street, W1N 8AA, London (United Kingdom); Ell, Peter J. [Institute of Nuclear Medicine, Royal Free and University College, Medical School, Mortimer Street, W1N 8AA, London (United Kingdom)

    2003-11-01

    Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT{sub 4}) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT{sub 4} receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT{sub 4} receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT{sub 4} receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [{sup 123}I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT{sub 4} receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT{sub 4} receptor antagonist, SB 204070, at 20 min before [{sup 123}I]SB 207710 injection

  7. Site-specific effects of the nonsteroidal anti-inflammatory drug lysine clonixinate on rat brain opioid receptors.

    Science.gov (United States)

    Ortí, E; Coirini, H; Pico, J C

    1999-04-01

    In addition to effects in the periphery through inhibition of prostaglandin synthesis, several lines of evidence suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) act in the central nervous system. The possibility that the central action of NSAIDs involves regulation of opioid receptors was investigated by quantitative autoradiography of mu, delta, and kappa sites in rat brain slices. Increased (p lysine clonixinate. Labeling of delta receptors was lower in the lateral septum, and kappa sites decreased in thalamic nuclei. These effects were not mediated through direct interaction with opioid-binding sites, since receptor-binding assays using rat brain membranes confirmed that clonixinate up to 1 x 10(-4) mol/l does not inhibit mu, delta, and kappa receptor specific binding. Central effects of NSAIDs might, therefore, involve interaction with the opioid receptor system through indirect mechanisms.

  8. The 5-HT1A serotonin receptor is located on calbindin- and parvalbumin-containing neurons in the rat brain

    DEFF Research Database (Denmark)

    Aznar, Susana; Qian, Zhaoxia; Shah, Reshma

    2003-01-01

    distributed in the rat brain, with a particularly high density in the limbic system. The receptor's localization in the different neuronal subtypes, which may be of importance for understanding its role in neuronal circuitries, is, however, unknown. In this study we show by immunocytochemical double......-labeling techniques, that the 5-HT(1A) receptor is present on both pyramidal and principal cells, and calbindin- and parvalbumin-containing neurons, which generally define two different subtypes of interneurons. Moreover, semiquantitative analysis showed that the receptor's distribution in the different neuronal...... types varies between brain areas. In cortex, hippocampus, hypothalamus, and amygdala the receptor was located on both principal cells and calbindin- and parvalbumin-containing neurons. In septum and thalamus, the receptor was mostly present on calbindin- and parvalbumin-containing cells. Especially...

  9. Differential ontogenetic patterns of levocabastine-sensitive neurotensin NT2 receptors and of NT1 receptors in the rat brain revealed by in situ hybridization.

    Science.gov (United States)

    Lépée-Lorgeoux, I; Betancur, C; Rostène, W; Pélaprat, D

    1999-03-12

    The postnatal ontogeny of the levocabastine-sensitive neurotensin receptor (NT2) mRNA was studied by in situ hybridization in the rat brain and compared with the distribution of the levocabastine-insensitive NT1 receptor. NT2 receptor mRNA was absent at birth from all brain structures except the ependymal cell layer lining the ventricles. The development of NT2 receptor mRNA followed three ontogenetic patterns. The first pattern, involving the majority of the cerebral gray matter, was characterized by a continuous increase from postnatal day 5 (P5) to P30. The second one, involving regions rich in myelinated fibers such as the corpus callosum and lacunosum moleculare layer of the hippocampus, exhibited a pronounced increase between P5 and P10, peaked at P15 and was followed by a plateau or a slight decrease. The third pattern was observed in the ependymal cell layer lining the olfactory and lateral ventricles, where the high labeling already present at birth continued to increase during development. These different developmental patterns could reflect the variety of cells expressing NT2 receptor mRNA, including neurons, protoplasmic astrocytes in gray matter, fibrous astrocytes present in myelinated fibers tracts, and ependymal cells. In contrast, NT1 receptor mRNA, which seems to be associated only with neurons, was highly and transiently expressed during the perinatal period in the cerebral cortex, hippocampus and striatal neuroepithelium. Other regions, notably the ventral tegmental area and substantia nigra compacta, exhibited a gradual increase in NT1 receptor signal, reaching adult levels by P21. Both the differential localization and ontogenetic profiles of NT1 and NT2 receptor mRNAs suggest different involvement of these two receptors in brain functions and development. Copyright 1999 Elsevier Science B.V.

  10. Cyto- and receptor architecture of area 32 in human and macaque brains.

    Science.gov (United States)

    Palomero-Gallagher, Nicola; Zilles, Karl; Schleicher, Axel; Vogt, Brent A

    2013-10-01

    Human area 32 plays crucial roles in emotion and memory consolidation. It has subgenual (s32), pregenual (p32), dorsal, and midcingulate components. We seek to determine whether macaque area 32 has subgenual and pregenual subdivisions and the extent to which they are comparable to those in humans by means of NeuN immunohistochemistry and multireceptor analysis of laminar profiles. The macaque has areas s32 and p32. In s32, layer IIIa/b neurons are larger than those of layer IIIc. This relationship is reversed in p32. Layer Va is thicker and Vb thinner in s32. Area p32 contains higher kainate, benzodiazepine (BZ), and serotonin (5-HT)1A but lower N-methyl-D-aspartate (NMDA) and α2 receptor densities. Most differences were found in layers I, II, and VI. Together, these differences support the dual nature of macaque area 32. Comparative analysis of human and macaque s32 and p32 supports equivalences in cyto- and receptor architecture. Although there are differences in mean areal receptor densities, there are considerable similarities at the layer level. Laminar receptor distribution patterns in each area are comparable in the two species in layers III-Va for kainate, NMDA, γ-aminobutyric acid (GABA)B , BZ, and 5-HT1A receptors. Multivariate statistical analysis of laminar receptor densities revealed that human s32 is more similar to macaque s32 and p32 than to human p32. Thus, macaque 32 is more complex than hitherto known. Our data suggest a homologous neural architecture in anterior cingulate s32 and p32 in human and macaque brains. © 2013 Wiley Periodicals, Inc.

  11. Characterization of solubilized human and rat brain US -endorphin-receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    Helmeste, D.M.; Li, C.H.

    1986-01-01

    Opioid receptors have been solubilized from human striatal and rat whole-brain membranes by use of 3-((3-cholamidopropyl)dimethylammonio)-1-propanesulfonate (CHAPS). Tritiated human US -endorphin (TH-US /sub h/-EP) binding revealed high-affinity competition by morphine, naloxone, and various US -EP analogues. Lack of high-affinity competition by (+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl)benzeneacetamide methanesulfonate (U50-488, Upjohn) indicated that k sites were not labeled by TH-US -/sub h/-EP under these conditions. Affinities were similar in both soluble and membrane preparations except for (Met)enkephalin, which appears to be rapidly degraded by the solubilized extract. Size differences between human and rat solubilized TH-US /sub h/-EP-receptor complexes were revealed by exclusion chromatography.

  12. Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

    DEFF Research Database (Denmark)

    Haahr, M. E.; Rasmussen, Peter Mondrup; Madsen, K.

    2012-01-01

    in food intake, and that pharmacological or genetic manipulation of the receptor in reward-related brain areas alters food intake.Here, we used positron emission tomography in humans to examine the association between cerebral 5-HT4Rs and common obesity.We found in humans a strong positive association......The neurobiology underlying obesity is not fully understood. The neurotransmitter serotonin (5-HT) is established as a satiety-generating signal, but its rewarding role in feeding is less well elucidated. From animal experiments there is now evidence that the 5-HT4 receptor (5-HT4R) is involved......'s food intake. They also suggest that pharmacological stimulation of the cerebral 5-HT4R may reduce reward-related overeating in humans....

  13. Comparative studies of D2 receptors and brain perfusion in hemi-parkinsonism rats

    International Nuclear Information System (INIS)

    Lin Yansong; Lin Xiangtong

    2000-01-01

    The relationship between dopamine D 2 receptors and brain perfusion in hemi-parkinsonism rats was studied. Hemi-parkinsonism rats were made by stereotaxic 6-hydroxy dopamine (6-OH-DA) lesions in substantia nigra (SN) and ventral tegmental area (VTA), apomorphine (Apo) which could induced the successful model rat rotates toward the intact side was used to select the rats, 125 I-IBZM ex-vivo autoradiography analysis and 99m Tc-HM-PAO regional cerebral biodistribution were used to evaluate D 2 receptors and cerebral blood flow. The HPLC-ECD were used to measure striatum DA and its metabolites content. The lesioned side striatum DA and its metabolites HVA DOPAC reduced significantly than that of the intact side and pseudo-operated group, striatum/cerebellum 125 I-IBZM uptake ratio was 8.04 +- 0.71 in lesioned side of hemi-parkinsonism rats, significantly increased compared with the intact side and the pseudo-operated group (p 0.05). These results indicated that in the 6-OH-DA lesioned side DA content decreased significantly and an up-regulation of striatum D 2 receptor binding sites was induced in hemi-parkinsonism rats, which showed good correlation with rotation behavior induced by Apo. Comparing with cerebral blood flow, D 2 receptor reflected by IBZM seems to be more specific and earlier to detect the cerebral functional impairment in experimental hemi-parkinsonism

  14. Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging.

    Science.gov (United States)

    Albayram, Onder; Alferink, Judith; Pitsch, Julika; Piyanova, Anastasia; Neitzert, Kim; Poppensieker, Karola; Mauer, Daniela; Michel, Kerstin; Legler, Anne; Becker, Albert; Monory, Krisztina; Lutz, Beat; Zimmer, Andreas; Bilkei-Gorzo, Andras

    2011-07-05

    Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1(-/-)), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1(-/-) mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1(-/-) mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.

  15. Long-lasting masculinizing effects of postnatal androgens on myelin governed by the brain androgen receptor

    Science.gov (United States)

    Abi Ghanem, Charly; Degerny, Cindy; Hussain, Rashad; Liere, Philippe; Pianos, Antoine; Tourpin, Sophie; Habert, René; Schumacher, Michael

    2017-01-01

    The oligodendrocyte density is greater and myelin sheaths are thicker in the adult male mouse brain when compared with females. Here, we show that these sex differences emerge during the first 10 postnatal days, precisely at a stage when a late wave of oligodendrocyte progenitor cells arises and starts differentiating. Androgen levels, analyzed by gas chromatography/tandem-mass spectrometry, were higher in males than in females during this period. Treating male pups with flutamide, an androgen receptor (AR) antagonist, or female pups with 5α-dihydrotestosterone (5α-DHT), revealed the importance of postnatal androgens in masculinizing myelin and their persistent effect into adulthood. A key role of the brain AR in establishing the sexual phenotype of myelin was demonstrated by its conditional deletion. Our results uncover a new persistent effect of postnatal AR signaling, with implications for neurodevelopmental disorders and sex differences in multiple sclerosis. PMID:29107990

  16. Human blood-brain barrier insulin-like growth factor receptor

    International Nuclear Information System (INIS)

    Duffy, K.R.; Pardridge, W.M.; Rosenfeld, R.G.

    1988-01-01

    Insulin-like growth factor (IGF)-1 and IGF-2, may be important regulatory molecules in the CNS. Possible origins of IGFs in brain include either de novo synthesis or transport of circulating IGFs from blood into brain via receptor mediated transcytosis mechanisms at the brain capillary endothelial wall, ie, the blood-brain barrier (BBB). In the present studies, isolated human brain capillaries are used as an in vitro model system of the human BBB and the characteristics of IGF-1 or IGF-2 binding to this preparation were assessed. The total binding of IGF-2 at 37 degrees C exceeded 130% per mg protein and was threefold greater than the total binding for IGF-1. However, at 37 degrees C nonsaturable binding equaled total binding, suggesting that endocytosis is rate limiting at physiologic temperatures. Binding studies performed at 4 degrees C slowed endocytosis to a greater extent than membrane binding, and specific binding of either IGF-1 or IGF-2 was detectable. Scatchard plots for either peptide were linear and the molar dissociation constant of IGF-1 and IGF-2 binding was 2.1 +/- 0.4 and 1.1 +/- 0.1 nmol/L, respectively. Superphysiologic concentrations of porcine insulin inhibited the binding of both IGF-1 (ED50 = 2 micrograms/mL) and IGF-2 (ED50 = 0.5 microgram/mL). Affinity cross linking of 125 I-IGF-1, 125 I-IGF-2, and 125 I-insulin to isolated human brain capillaries was performed using disuccinimidylsuberate (DSS). These studies revealed a 141 kd binding site for both IGF-1 and IGF-2, and a 133 kd binding site for insulin

  17. Glucocorticoid receptor gene expression and promoter CpG modifications throughout the human brain.

    Science.gov (United States)

    Cao-Lei, Lei; Suwansirikul, Songkiet; Jutavijittum, Prapan; Mériaux, Sophie B; Turner, Jonathan D; Muller, Claude P

    2013-11-01

    Glucocorticoids and the glucocorticoid (GR) and mineralocorticoid (MR) receptors have been implicated in many processes, particularly in negative feedback regulation of the hypothalamic-pituitary-adrenal axis. Epigenetically programmed GR alternative promoter usage underlies transcriptional control of GR levels, generation of GR 3' splice variants, and the overall GC response in the brain. No detailed analysis of GR first exons or GR transcript variants throughout the human brain has been reported. Therefore we investigated post mortem tissues from 28 brain regions of 5 individuals. GR first exons were expressed throughout the healthy human brain with no region-specific usage patterns. First exon levels were highly inter-correlated suggesting that they are co-regulated. GR 3' splice variants (GRα and GR-P) were equally distributed in all regions, and GRβ expression was always low. GR/MR ratios showed significant differences between the 28 tissues with the highest ratio in the pituitary gland. Modification levels of individual CpG dinucleotides, including 5-mC and 5-hmC, in promoters 1D, 1E, 1F, and 1H were low, and diffusely clustered; despite significant heterogeneity between the donors. In agreement with this clustering, sum modification levels rather than individual CpG modifications correlated with GR expression. Two-way ANOVA showed that this sum modification was both promoter and brain region specific, but that there was however no promoter*tissue interaction. The heterogeneity between donors may however hide such an interaction. In both promoters 1F and 1H modification levels correlated with GRα expression suggesting that 5-mC and 5-hmC play an important role in fine tuning GR expression levels throughout the brain. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

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    Jaume Folch

    2018-01-01

    Full Text Available Alzheimer’s disease (AD is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ, which form senile plaques, neurofibrillary tangles (NFT and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Aβ production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD pathogenesis, more data is being obtained. Recent evidence showed that Aβ42 generated in the brain would impact negatively on the hypothalamus, accelerating the “peripheral” symptomatology of AD. In this situation, Aβ42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors.

  19. Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors

    Science.gov (United States)

    Stanić, Davor; Dubois, Sydney; Chua, Hui Kheng; Tonge, Bruce; Rinehart, Nicole; Horne, Malcolm K.; Boon, Wah Chin

    2014-01-01

    Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, including the bed nucleus of the stria terminalis, olfactory tubercle, medial amygdaloid nucleus and medial preoptic area, with the densest distributions of EGFP-positive cell bodies in the bed nucleus and medial amygdala. Differences between male and female mice were apparent, with the density of EGFP-positive cell bodies and fibres being lower in some brain regions of female mice, including the bed nucleus and medial amygdala. EGFP-positive cell bodies in the bed nucleus, lateral septum, medial amygdala and hypothalamus co-expressed oestrogen receptor (ER) α and β, or the androgen receptor (AR), although single-labelled EGFP-positive cells were also identified. Additionally, single-labelled ERα−, ERβ- or AR-positive cell bodies often appeared to be surrounded by EGFP-immunoreactive nerve fibres/terminals. The widespread distribution of EGFP-positive cell bodies and fibres suggests that aromatase signalling is common in the mouse brain, and that locally synthesised brain oestrogens could mediate biological effects by activating pre- and post-synaptic oestrogen α and β receptors, and androgen receptors. The higher number of EGFP-positive cells in male mice may indicate that the autocrine and paracrine effects of oestrogens are more prominent in males than females. PMID:24646567

  20. Characterization of GABA/sub A/ receptor-mediated 36chloride uptake in rat brain synaptoneurosomes

    International Nuclear Information System (INIS)

    Luu, M.D.; Morrow, A.L.; Paul, S.M.; Schwartz, R.D.

    1987-01-01

    γ-Aminobutyric acid (GABA) receptor-mediated 36 chloride ( 36 Cl - ) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated 36 Cl - uptake in a concentration-dependent manner with the following order of potency: Muscimol>GABA>piperidine-4-sulfonic acid (P4S)>4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP)=3-aminopropanesulfonic acid (3APS)>>taurine. Both P4S and 3APS behaved as partial agonists, while the GABA/sub B/ agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated 36 Cl - uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated 36 Cl - uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br - >Cl - ≥NO 3 - >I - ≥SCN - >>C 3 H 5 OO - ≥ClO 4 - >F - , consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl - channel. 43 references, 4 figures, 3 tables

  1. From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

    Directory of Open Access Journals (Sweden)

    Ken Howick

    2017-01-01

    Full Text Available Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrallymediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.

  2. Neuropeptide Y (NPY) and peptide YY (PYY) receptors in rat brain

    International Nuclear Information System (INIS)

    Ohkubo, T.; Niwa, M.; Yamashita, K.; Kataoka, Y.; Shigematsu, K.

    1990-01-01

    1. Specific binding sites for neuropeptide Y (NPY) and peptide YY (PYY) were investigated in rat brain areas using quantitative receptor autoradiography with 125 I-Bolton-Hunter NPY ( 125 I-BH-NPY) and 125 I-PYY, radioligands for PP-fold family peptides receptors. 2. There were no differences between localization of 125 I-BH-NPY and 125 I-PYY binding sites in the rat brain. High densities of the binding sites were present in the anterior olfactory nucleus, lateral septal nucleus, stratum radiatum of the hippocampus, posteromedial cortical amygdaloid nucleus, and area postrema. 3. In cold ligand-saturation experiments done in the presence of increasing concentrations of unlabeled NPY and PYY, 125 I-BH-NPY and 125 I-PYY binding to the stratum radiatum of the hippocampus, layer I of the somatosensory frontoparietal cortex, molecular layer of the cerebellum, and area postrema was single and of a high affinity. There was a significant difference between the affinities of 125 I-BH-NPY (Kd = 0.96 nM) and 125 I-PYY binding (Kd = 0.05 nM) to the molecular layer of the cerebellum. The binding of the two radioligands to the other areas examined had the same affinities. 4. When comparing the potency of unlabeled rat pancreatic polypeptide (rPP), a family peptide of NPY and PYY, to inhibit the binding to the areas examined, rPP displaced 125 I-BH-NPY and 125 I-PYY binding to the area postrema more potently than it did the binding to the stratum radiatum of the hippocampus, layer I of the somatosensory frontoparietal cortex, and molecular layer of the cerebellum. 5. Thus, the quantitative receptor autoradiographic method with 125 I-BH-NPY and 125 I-PYY revealed differences in binding characteristics of specific NPY and PYY binding sites in different areas of the rat brain. The results provide further evidence for the existence of multiple NPY-PYY receptors in the central nervous system

  3. Selective Estrogen Receptor Modulators regulate reactive microglia after penetrating brain injury

    Directory of Open Access Journals (Sweden)

    George E. Barreto

    2014-06-01

    Full Text Available Following brain injury, microglia assume a reactive-like state and secrete pro-inflammatory molecules that can potentiate damage. A therapeutic strategy that may limit microgliosis is of potential interest. In this context, selective estrogen receptor modulators, such as raloxifene and tamoxifen, are known to reduce microglia activation induced by neuroinflammatory stimuli in young animals. In the present study, we have assessed whether raloxifene and tamoxifen are able to affect microglia activation after brain injury in young and aged animals in time points relevant to clinics, which is hours after brain trauma. Volume fraction of MHC-II+ microglia was estimated according to the point-counting method of Weibel within a distance of 350 μm from the lateral border of the wound, and cellular morphology was measured by fractal analysis. Two groups of animals were studied: 1 young rats, ovariectomized at 2 months of age; and 2 aged rats, ovariectomized at 18 months of age. Fifteen days after ovariectomy animals received a stab wound brain injury and the treatment with estrogenic compounds. Our findings indicate that raloxifene and tamoxifen reduced microglia activation in both young and aged animals. Although the volume fraction of reactive microglia was found lower in aged animals, this was accompanied by important changes in cell morphology, where aged microglia assume a bushier and hyperplasic aspect when compared to young microglia. These data suggest that early regulation of microglia activation provides a mechanism by which SERMs may exert a neuroprotective effect in the setting of a brain trauma.

  4. Small-animal PET study of adenosine A(1) receptors in rat brain: blocking receptors and raising extracellular adenosine.

    Science.gov (United States)

    Paul, Soumen; Khanapur, Shivashankar; Rybczynska, Anna A; Kwizera, Chantal; Sijbesma, Jurgen W A; Ishiwata, Kiichi; Willemsen, Antoon T M; Elsinga, Philip H; Dierckx, Rudi A J O; van Waarde, Aren

    2011-08-01

    Activation of adenosine A(1) receptors (A(1)R) in the brain causes sedation, reduces anxiety, inhibits seizures, and promotes neuroprotection. Cerebral A(1)R can be visualized using 8-dicyclopropylmethyl-1-(11)C-methyl-3-propyl-xanthine ((11)C-MPDX) and PET. This study aims to test whether (11)C-MPDX can be used for quantitative studies of cerebral A(1)R in rodents. (11)C-MPDX was injected (intravenously) into isoflurane-anesthetized male Wistar rats (300 g). A dynamic scan of the central nervous system was obtained, using a small-animal PET camera. A cannula in a femoral artery was used for blood sampling. Three groups of animals were studied: group 1, controls (saline-treated); group 2, animals pretreated with the A(1)R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 mg, intraperitoneally); and group 3, animals pretreated (intraperitoneally) with a 20% solution of ethanol in saline (2 mL) plus the adenosine kinase inhibitor 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d] pyrimidine dihydrochloride (ABT-702) (1 mg). DPCPX is known to occupy cerebral A(1)R, whereas ethanol and ABT-702 increase extracellular adenosine. In groups 1 and 3, the brain was clearly visualized. High uptake of (11)C-MPDX was noted in striatum, hippocampus, and cerebellum. In group 2, tracer uptake was strongly suppressed and regional differences were abolished. The treatment of group 3 resulted in an unexpected 40%-45% increase of the cerebral uptake of radioactivity as indicated by increases of PET standardized uptake value, distribution volume from Logan plot, nondisplaceable binding potential from 2-tissue-compartment model fit, and standardized uptake value from a biodistribution study performed after the PET scan. The partition coefficient of the tracer (K(1)/k(2) from the model fit) was not altered under the study conditions. (11)C-MPDX shows a regional distribution in rat brain consistent with binding to A(1)R. Tracer binding is blocked by the selective A

  5. BIASED AGONISM OF THREE DIFFERENT CANNABINOID RECEPTOR AGONISTS IN MOUSE BRAIN CORTEX

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    Rebeca Diez-Alarcia

    2016-11-01

    Full Text Available Cannabinoid receptors are able to couple to different families of G-proteins when activated by an agonist drug. It has been suggested that different intracellular responses may be activated depending on the ligand. The goal of the present study was to characterize the pattern of G protein subunit stimulation triggered by three different cannabinoid ligands, THC, WIN55212-2 and ACEA in mouse brain cortex.Stimulation of the [35S]GTPS binding coupled to specific immunoprecipitation with antibodies against different subtypes of G proteins (Gαi1, Gαi2, Gαi3, Gαo, Gαz, Gαs, Gαq/11, and Gα12/13, in the presence of Δ9-THC, WIN55212-2 and ACEA (submaximal concentration 10 µM was determined by Scintillation Proximity Assay (SPA technique in mouse cortex of wild type, CB1 knock-out, CB2 knock-out and CB1/CB2 double knock-out mice. Results show that, in mouse brain cortex, cannabinoid agonists are able to significantly stimulate not only the classical inhibitory Gαi/o subunits but also other G subunits like Gαz, Gαq/11, and Gα12/13. Moreover, the specific pattern of G protein subunit activation is different depending on the ligand. In conclusion, our results demonstrate that, in mice brain native tissue, different exogenous cannabinoid ligands are able to selectively activate different inhibitory and non-inhibitory Gα protein subtypes, through the activation of CB1 and/or CB2 receptors. Results of the present study may help to understand the specific molecular pathways involved in the pharmacological effects of cannabinoid-derived drugs.

  6. Affinity purification and partial characterization of the zonulin/zonula occludens toxin (Zot) receptor from human brain.

    Science.gov (United States)

    Lu, R; Wang, W; Uzzau, S; Vigorito, R; Zielke, H R; Fasano, A

    2000-01-01

    The intercellular tight junctions (TJs) of endothelial cells represent the limiting structure for the permeability of the blood-brain barrier (BBB). Although the BBB has been recognized as being the interface between the bloodstream and the brain, little is known about its regulation. Zonulin and its prokaryotic analogue, zonula occludens toxin (Zot) elaborated by Vibrio cholerae, both modulate intercellular TJs by binding to a specific surface receptor with subsequent activation of an intracellular signaling pathway involving phospholipase C and protein kinase C activation and actin polymerization. Affinity column purification revealed that human brain plasma membrane preparations contain two Zot binding proteins of approximately 55 and approximately 45 kDa. Structural and kinetic studies, including saturation and competitive assays, identified the 55-kDa protein as tubulin, whereas the 45-kDa protein represents the zonulin/Zot receptor. Biochemical characterization provided evidence that this receptor is a glycoprotein containing multiple sialic acid residues. Comparison of the N-terminal sequence of the zonulin/Zot receptor with other protein sequences by BLAST analysis revealed a striking similarity with MRP-8, a 14-kDa member of the S-100 family of calcium binding proteins. The discovery and characterization of this receptor from human brain may significantly contribute to our knowledge on the pathophysiological regulation of the BBB.

  7. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

    Directory of Open Access Journals (Sweden)

    Laurent Kappeler

    2008-10-01

    Full Text Available Mutations that decrease insulin-like growth factor (IGF and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

  8. Altered organization of GABAA receptor mRNA expression in the depressed suicide brain

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    Michael O Poulter

    2010-03-01

    Full Text Available Inter-relationships ordinarily exist between mRNA expression of GABA-A subunits in the frontopolar cortex (FPC of individuals that had died suddenly from causes other than suicide. However, these correlations were largely absent in persons that had died by suicide. In the present investigation, these findings were extended by examining GABA-A receptor expression patterns (of controls and depressed individuals that died by suicide in the orbital frontal cortex (OFC, hippocampus, amygdala. locus coeruleus (LC,and paraventricular nucleus (PVN, all of which have been implicated in either depression, anxiety or stress responsivity. Results Using QPCR analysis, we found that in controls the inter-relations between GABA-A subunits varied across brain regions, being high in the hippocampus and amygdala, intermediate in the LC, and low in the OFC and PVN. The GABA-A subunit inter-relations were markedly different in persons that died by suicide, being reduced in hippocampus and amygdala, stable in the LC, but more coordinated in the OFC and to some extent in the PVN. Conclusions It seems that altered brain region-specific inhibitory signaling, stemming from altered GABA-A subunit coordination, are associated with depression/suicide. Although, it is unknown whether GABA-A subunit re-organization was specifically tied to depression, suicide, or the accompanying distress, these data show that the co-ordinate expression of this transcriptome does vary depending on brain region and is plastic.

  9. Nuclear progesterone receptors are up-regulated by estrogens in neurons and radial glial progenitors in the brain of zebrafish.

    Directory of Open Access Journals (Sweden)

    Nicolas Diotel

    Full Text Available In rodents, there is increasing evidence that nuclear progesterone receptors are transiently expressed in many regions of the developing brain, notably outside the hypothalamus. This suggests that progesterone and/or its metabolites could be involved in functions not related to reproduction, particularly in neurodevelopment. In this context, the adult fish brain is of particular interest, as it exhibits constant growth and high neurogenic activity that is supported by radial glia progenitors. However, although synthesis of neuroprogestagens has been documented recently in the brain of zebrafish, information on the presence of progesterone receptors is very limited. In zebrafish, a single nuclear progesterone receptor (pgr has been cloned and characterized. Here, we demonstrate that this pgr is widely distributed in all regions of the zebrafish brain. Interestingly, we show that Pgr is strongly expressed in radial glial cells and more weakly in neurons. Finally, we present evidence, based on quantitative PCR and immunohistochemistry, that nuclear progesterone receptor mRNA and proteins are upregulated by estrogens in the brain of adult zebrafish. These data document for the first time the finding that radial glial cells are preferential targets for peripheral progestagens and/or neuroprogestagens. Given the crucial roles of radial glial cells in adult neurogenesis, the potential effects of progestagens on their activity and the fate of daughter cells require thorough investigation.

  10. Topographical distribution of decrements and recovery in muscarinic receptors from rat brains repeatedly exposed to sublethal doses of soman

    International Nuclear Information System (INIS)

    Churchill, L.; Pazdernik, T.L.; Jackson, J.L.; Nelson, S.R.; Samson, F.E.; McDonough, J.H. Jr.

    1984-01-01

    [3H]Quinuclidinyl benzilate binding to rat brain muscarinic receptors decreased after repeated exposure to soman, a potent organophosphorus cholinesterase inhibitor. The topographical distribution of this decrement was analyzed by quantitative receptor autoradiography. After 4 weeks of soman, three times a week, quinuclidinyl benzilate binding decreased to 67 to 80% of control in frontal and parietal cortex, caudate-putamen, lateral septum, hippocampal body, dentate gyrus, superior colliculus, nucleus of the fifth nerve, and central grey. Minor or no decreases were observed in thalamic or hypothalamic nuclei, reticular formation, pontine nuclei, inferior colliculus, nucleus of the seventh nerve, and cerebellum. Scatchard analyses of saturation curves using frontal cortex sections from soman-treated rats revealed a decrease in maximal quinuclidinyl benzilate binding from that in control rats and a return toward control levels by 24 days without any significant change in affinity. These brain areas showing significant decrements in muscarinic receptors recovered with a similar time course. An estimate of the time for 50% recovery for some of the brain areas was 14 days for superior colliculus, 16 days for cortex, and 19 days for hippocampal body. The application of quantitative receptor autoradiography to analyze receptor alterations has been valuable in localizing the telencephalon as a region more susceptible to change in receptor concentration

  11. Topographical distribution of decrements and recovery in muscarinic receptors from rat brains repeatedly exposed to sublethal doses of soman

    Energy Technology Data Exchange (ETDEWEB)

    Churchill, L.; Pazdernik, T.L.; Jackson, J.L.; Nelson, S.R.; Samson, F.E.; McDonough, J.H. Jr.

    1984-08-01

    (3H)Quinuclidinyl benzilate binding to rat brain muscarinic receptors decreased after repeated exposure to soman, a potent organophosphorus cholinesterase inhibitor. The topographical distribution of this decrement was analyzed by quantitative receptor autoradiography. After 4 weeks of soman, three times a week, quinuclidinyl benzilate binding decreased to 67 to 80% of control in frontal and parietal cortex, caudate-putamen, lateral septum, hippocampal body, dentate gyrus, superior colliculus, nucleus of the fifth nerve, and central grey. Minor or no decreases were observed in thalamic or hypothalamic nuclei, reticular formation, pontine nuclei, inferior colliculus, nucleus of the seventh nerve, and cerebellum. Scatchard analyses of saturation curves using frontal cortex sections from soman-treated rats revealed a decrease in maximal quinuclidinyl benzilate binding from that in control rats and a return toward control levels by 24 days without any significant change in affinity. These brain areas showing significant decrements in muscarinic receptors recovered with a similar time course. An estimate of the time for 50% recovery for some of the brain areas was 14 days for superior colliculus, 16 days for cortex, and 19 days for hippocampal body. The application of quantitative receptor autoradiography to analyze receptor alterations has been valuable in localizing the telencephalon as a region more susceptible to change in receptor concentration.

  12. Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain.

    Science.gov (United States)

    Buckholtz, N S; Zhou, D F; Freedman, D X; Potter, W Z

    1990-04-01

    A dosage regimen of lysergic acid diethylamide (LSD) that reliably produces behavioral tolerance in rats was evaluated for effects on neurotransmitter receptor binding in rat brain using a variety of radioligands selective for amine receptor subtypes. Daily administration of LSD [130 micrograms/kg (0.27 mumol/kg) intraperitoneally (IP)] for 5 days produced a decrease in serotonin2 (5-hydroxytryptamine2, 5-HT2) binding in cortex (measured 24 hours after the last drug administration) but did not affect binding to other receptor systems (5-HT1A, 5-HT1B, beta-adrenergic, alpha 1- or alpha 2-adrenergic, D2-dopaminergic) or to a recognition site for 5-HT uptake. The decrease was evident within 3 days of LSD administration but was not demonstrable after the first LSD dose. Following 5 days of LSD administration the decrease was still present 48 hours, but not 96 hours, after the last administration. The indole hallucinogen psilocybin [1.0 mg/kg (3.5 mumol/kg) for 8 days] also produced a significant decrease in 5HT2 binding, but neither the nonhallucinogenic analog bromo-LSD [1.3 mg/kg (2.4 mumol/kg) for 5 days] nor mescaline [10 mg/kg (40.3 mumol/kg) for 5 or 10 days] affected 5-HT2 binding. These observations suggest that LSD and other indole hallucinogens may act as 5-HT2 agonists at postsynaptic 5-HT2 receptors. Decreased 5-HT2 binding strikingly parallels the development and loss of behavioral tolerance seen with repeated LSD administration, but the decreased binding per se cannot explain the gamut of behavioral tolerance and cross-tolerance phenomena among the indole and phenylethylamine hallucinogens.

  13. Elevated Brain Cannabinoid CB1 Receptor Availability in Posttraumatic Stress Disorder: A Positron Emission Tomography Study

    Science.gov (United States)

    Neumeister, Alexander; Normandin, Marc D.; Pietrzak, Robert H.; Piomelli, Daniele; Zheng, Ming-Qiang; Gujarro-Anton, Ana; Potenza, Marc N.; Bailey, Christopher R.; Lin, Shu-fei; Najafzadeh, Soheila; Ropchan, Jim; Henry, Shannan; Corsi-Travali, Stefani; Carson, Richard E.; Huang, Yiyun

    2013-01-01

    Endocannabinoids and their attending cannabinoid type 1 receptor (CB1) have been implicated in animal models of posttraumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [11C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma controls [TC]) and those without such histories (healthy controls [HC]). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance (MR) imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [11C]OMAR, which measures volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [11C]OMAR VT values (F(2,53)=7.96, p=.001; 19.5% and 14.5% higher, respectively) which were most pronounced in women (F(1,53)=5.52, p=.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively—OMAR VT, anandamide, and cortisol—correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder. PMID:23670490

  14. Anandamide inhibits Theiler's virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB1 receptors

    Directory of Open Access Journals (Sweden)

    Loría Frida

    2011-08-01

    Full Text Available Abstract Background VCAM-1 represents one of the most important adhesion molecule involved in the transmigration of blood leukocytes across the blood-brain barrier (BBB that is an essential step in the pathogenesis of MS. Several evidences have suggested the potential therapeutic value of cannabinoids (CBs in the treatment of MS and their experimental models. However, the effects of endocannabinoids on VCAM-1 regulation are poorly understood. In the present study we investigated the effects of anandamide (AEA in the regulation of VCAM-1 expression induced by Theiler's virus (TMEV infection of brain endothelial cells using in vitro and in vivo approaches. Methods i in vitro: VCAM-1 was measured by ELISA in supernatants of brain endothelial cells infected with TMEV and subjected to AEA and/or cannabinoid receptors antagonist treatment. To evaluate the functional effect of VCAM-1 modulation we developed a blood brain barrier model based on a system of astrocytes and brain endothelial cells co-culture. ii in vivo: CB1 receptor deficient mice (Cnr1-/- infected with TMEV were treated with the AEA uptake inhibitor UCM-707 for three days. VCAM-1 expression and microglial reactivity were evaluated by immunohistochemistry. Results Anandamide-induced inhibition of VCAM-1 expression in brain endothelial cell cultures was mediated by activation of CB1 receptors. The study of leukocyte transmigration confirmed the functional relevance of VCAM-1 inhibition by AEA. In vivo approaches also showed that the inhibition of AEA uptake reduced the expression of brain VCAM-1 in response to TMEV infection. Although a decreased expression of VCAM-1 by UCM-707 was observed in both, wild type and CB1 receptor deficient mice (Cnr1-/-, the magnitude of VCAM-1 inhibition was significantly higher in the wild type mice. Interestingly, Cnr1-/- mice showed enhanced microglial reactivity and VCAM-1 expression following TMEV infection, indicating that the lack of CB1 receptor

  15. Posttraumatic Propofol Neurotoxicity Is Mediated via the Pro-Brain-Derived Neurotrophic Factor-p75 Neurotrophin Receptor Pathway in Adult Mice.

    Science.gov (United States)

    Sebastiani, Anne; Granold, Matthias; Ditter, Anja; Sebastiani, Philipp; Gölz, Christina; Pöttker, Bruno; Luh, Clara; Schaible, Eva-Verena; Radyushkin, Konstantin; Timaru-Kast, Ralph; Werner, Christian; Schäfer, Michael K; Engelhard, Kristin; Moosmann, Bernd; Thal, Serge C

    2016-02-01

    The gamma-aminobutyric acid modulator propofol induces neuronal cell death in healthy immature brains by unbalancing neurotrophin homeostasis via p75 neurotrophin receptor signaling. In adulthood, p75 neurotrophin receptor becomes down-regulated and propofol loses its neurotoxic effect. However, acute brain lesions, such as traumatic brain injury, reactivate developmental-like programs and increase p75 neurotrophin receptor expression, probably to foster reparative processes, which in turn could render the brain sensitive to propofol-mediated neurotoxicity. This study investigates the influence of delayed single-bolus propofol applications at the peak of p75 neurotrophin receptor expression after experimental traumatic brain injury in adult mice. Randomized laboratory animal study. University research laboratory. Adult C57BL/6N and nerve growth factor receptor-deficient mice. Sedation by IV propofol bolus application delayed after controlled cortical impact injury. Propofol sedation at 24 hours after traumatic brain injury increased lesion volume, enhanced calpain-induced αII-spectrin cleavage, and increased cell death in perilesional tissue. Thirty-day postinjury motor function determined by CatWalk (Noldus Information Technology, Wageningen, The Netherlands) gait analysis was significantly impaired in propofol-sedated animals. Propofol enhanced pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor ratio, which aggravates p75 neurotrophin receptor-mediated cell death. Propofol toxicity was abolished both by pharmacologic inhibition of the cell death domain of the p75 neurotrophin receptor (TAT-Pep5) and in mice lacking the extracellular neurotrophin binding site of p75 neurotrophin receptor. This study provides first evidence that propofol sedation after acute brain lesions can have a deleterious impact and implicates a role for the pro-brain-derived neurotrophic factor-p75 neurotrophin receptor pathway. This observation is important as sedation

  16. Brain α1-adrenergic receptors: suitability of [125I]HEAT as a radioligand for in vitro autoradiography

    International Nuclear Information System (INIS)

    Jones, L.S.; Gauger, L.L.; Davis, J.N.

    1983-01-01

    [2-(β-4-Hydroxyphenyl)-ethylaminomethyl)-tetralone] (BE 2254, HEAT) is a new potent α 1 -adrenergic receptor blocker. The iodinated radioligand, [ 125 I]HEAT appears to be even more potent than HEAT (Engel and Hoyer, 1981; Glossman et al., 1981) and has proved useful for the studying of α 1 -adrenergic receptors in membrane preparations of rat brain. The authors report the suitability of [ 125 I]HEAT for α 1 -adrenergic binding site autoradiography and a degree of localization of α 1 -adrenergic receptor binding sites that has not been possible with [ 3 H]WB 4101 and [ 3 H]prazosin autoradiography. (Auth.)

  17. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans

    NARCIS (Netherlands)

    van Bloemendaal, L.; Veltman, D. J.; ten Kulve, J. S.; Groot, P. F. C.; Ruhe, H. G.; Barkhof, F.; Sloan, J. H.; Diamant, M.; Ijzerman, R. G.

    AimTo test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. MethodsAs part of a larger study, we determined the effects of GLP-1 receptor activation on brain

  18. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans

    NARCIS (Netherlands)

    van Bloemendaal, L.; Veltman, D. J.; ten Kulve, J. S.; Groot, P. F. C.; Ruhé, H. G.; Barkhof, F.; Sloan, J. H.; Diamant, M.; Ijzerman, R. G.

    2015-01-01

    To test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. As part of a larger study, we determined the effects of GLP-1 receptor activation on brain responses to

  19. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans

    NARCIS (Netherlands)

    van Bloemendaal, L.; Veltman, D.J.; ten Kulve, J.S.; Groot, P.F.C.; Ruhe, H.G.; Barkhof, F.; Sloan, J.H.; Diamant, M.; IJzerman, R.G.

    2015-01-01

    Aim: To test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. Methods: As part of a larger study, we determined the effects of GLP-1 receptor activation on brain

  20. Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior.

    Science.gov (United States)

    Dumais, Kelly M; Veenema, Alexa H

    2016-01-01

    The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species-specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain.

    Science.gov (United States)

    Kim, Youngsoo; Elmenhorst, David; Weisshaupt, Angela; Wedekind, Franziska; Kroll, Tina; McCarley, Robert W; Strecker, Robert E; Bauer, Andreas

    2015-10-01

    Although chronic sleep restriction frequently produces long-lasting behavioural and physiological impairments in humans, the underlying neural mechanisms are unknown. Here we used a rat model of chronic sleep restriction to investigate the role of brain adenosine and noradrenaline systems, known to regulate sleep and wakefulness, respectively. The density of adenosine A1 and A2a receptors and β-adrenergic receptors before, during and following 5 days of sleep restriction was assessed with autoradiography. Rats (n = 48) were sleep-deprived for 18 h day(-1) for 5 consecutive days (SR1-SR5), followed by 3 unrestricted recovery sleep days (R1-R3). Brains were collected at the beginning of the light period, which was immediately after the end of sleep deprivation on sleep restriction days. Chronic sleep restriction increased adenosine A1 receptor density significantly in nine of the 13 brain areas analysed with elevations also observed on R3 (+18 to +32%). In contrast, chronic sleep restriction reduced adenosine A2a receptor density significantly in one of the three brain areas analysed (olfactory tubercle which declined 26-31% from SR1 to R1). A decrease in β-adrenergic receptors density was seen in substantia innominata and ventral pallidum which remained reduced on R3, but no changes were found in the anterior cingulate cortex. These data suggest that chronic sleep restriction can induce long-term changes in the brain adenosine and noradrenaline receptors, which may underlie the long-lasting neurocognitive impairments observed in chronic sleep restriction. © 2015 European Sleep Research Society.

  2. Vasopressin and oxytocin receptor systems in the brain: sex differences and sex-specific regulation of social behavior

    Science.gov (United States)

    Dumais, Kelly M.; Veenema, Alexa H.

    2015-01-01

    The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species- specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans. PMID:25951955

  3. Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.

    Science.gov (United States)

    Saldana, Sandra M; Lee, Heng-Huan; Lowery, Frank J; Khotskaya, Yekaterina B; Xia, Weiya; Zhang, Chenyu; Chang, Shih-Shin; Chou, Chao-Kai; Steeg, Patricia S; Yu, Dihua; Hung, Mien-Chie

    2013-01-01

    Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.

  4. Drosophila insulin release is triggered by adipose Stunted ligand to brain Methuselah receptor.

    Science.gov (United States)

    Delanoue, Renald; Meschi, Eleonora; Agrawal, Neha; Mauri, Alessandra; Tsatskis, Yonit; McNeill, Helen; Léopold, Pierre

    2016-09-30

    Animals adapt their growth rate and body size to available nutrients by a general modulation of insulin-insulin-like growth factor signaling. In Drosophila, dietary amino acids promote the release in the hemolymph of brain insulin-like peptides (Dilps), which in turn activate systemic organ growth. Dilp secretion by insulin-producing cells involves a relay through unknown cytokines produced by fat cells. Here, we identify Methuselah (Mth) as a secretin-incretin receptor subfamily member required in the insulin-producing cells for proper nutrient coupling. We further show, using genetic and ex vivo organ culture experiments, that the Mth ligand Stunted (Sun) is a circulating insulinotropic peptide produced by fat cells. Therefore, Sun and Mth define a new cross-organ circuitry that modulates physiological insulin levels in response to nutrients. Copyright © 2016, American Association for the Advancement of Science.

  5. Effect of chronic psychogenic stress on characteristics of some rat brain synaptic membrane receptors

    International Nuclear Information System (INIS)

    Nikuradze, V.O.; Kozlovskaya, M.M.; Rozhanets, V.V.; Val'dman, A.V.

    1986-01-01

    This paper studies characteristics of alpha- and beta-adrenoreceptors, and imipramine and bensodiazepine receptors in brain synaptic membranes of rats after exposure to combined stress for 15 days by a modified Hecht's method. Before the experiment the suspension was thawed and centrifuged. Specific binding of tritium-WB-4101 (30 Ci/mmole), tritium-dihydroalprenolol, tritium-flunitrazepam, and tritium-imipramine was carried out by known methods with certain modifications. The results suggest that pathology of behavior in rats observed in the model may be classed as a depressive-like state rather than a neurosis-like state, and the model itself may be more appropriate for the study of the mechanisms of action of compounds with marked tranquilizing activity

  6. Effect of chronic psychogenic stress on characteristics of some rat brain synaptic membrane receptors

    Energy Technology Data Exchange (ETDEWEB)

    Nikuradze, V.O.; Kozlovskaya, M.M.; Rozhanets, V.V.; Val' dman, A.V.

    1986-02-01

    This paper studies characteristics of alpha- and beta-adrenoreceptors, and imipramine and bensodiazepine receptors in brain synaptic membranes of rats after exposure to combined stress for 15 days by a modified Hecht's method. Before the experiment the suspension was thawed and centrifuged. Specific binding of tritium-WB-4101 (30 Ci/mmole), tritium-dihydroalprenolol, tritium-flunitrazepam, and tritium-imipramine was carried out by known methods with certain modifications. The results suggest that pathology of behavior in rats observed in the model may be classed as a depressive-like state rather than a neurosis-like state, and the model itself may be more appropriate for the study of the mechanisms of action of compounds with marked tranquilizing activity.

  7. Pharmacological manipulation of serotonin receptors during brain embryogenesis favours stress resiliency in female rats

    Directory of Open Access Journals (Sweden)

    Gianluca Lavanco

    2018-02-01

    Full Text Available Manipulations of the serotonin transmission during early development induce long-lasting changes in the serotonergic circuitry throughout the brain. However, little is known on the developmental consequences in the female progeny. Therefore, this study aimed at exploring the behavioural effects of pre- and postnatal stimulation of the serotonergic system by 5-methoxytryptamine in adolescent female rats on behavioural reactivity and anxiety- like phenotype. Our results show that perinatal 5- methoxythyptamine decreased total distance travelled and rearing frequency in the novel enviroment, and increased the preference for the centre of the arena in the open field test. Moreover, perinatal 5-methoxytryptamine increased the percentages of entries and time spent on the open arms of the elevated plus maze, with respect to perinatally vehicle-exposed rats. Thus, perinatal stimulation of serotonin receptors does not impair the functional response to the emotional challenges in female rats, favouring the occurrence of a stress-resilient phenotype.

  8. Sustained NMDA receptor hypofunction induces compromised neural systems integration and schizophrenia-like alterations in functional brain networks.

    Science.gov (United States)

    Dawson, Neil; Xiao, Xiaolin; McDonald, Martin; Higham, Desmond J; Morris, Brian J; Pratt, Judith A

    2014-02-01

    Compromised functional integration between cerebral subsystems and dysfunctional brain network organization may underlie the neurocognitive deficits seen in psychiatric disorders. Applying topological measures from network science to brain imaging data allows the quantification of complex brain network connectivity. While this approach has recently been used to further elucidate the nature of brain dysfunction in schizophrenia, the value of applying this approach in preclinical models of psychiatric disease has not been recognized. For the first time, we apply both established and recently derived algorithms from network science (graph theory) to functional brain imaging data from rats treated subchronically with the N-methyl-D-aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). We show that subchronic PCP treatment induces alterations in the global properties of functional brain networks akin to those reported in schizophrenia. Furthermore, we show that subchronic PCP treatment induces compromised functional integration between distributed neural systems, including between the prefrontal cortex and hippocampus, that have established roles in cognition through, in part, the promotion of thalamic dysconnectivity. We also show that subchronic PCP treatment promotes the functional disintegration of discrete cerebral subsystems and also alters the connectivity of neurotransmitter systems strongly implicated in schizophrenia. Therefore, we propose that sustained NMDA receptor hypofunction contributes to the pathophysiology of dysfunctional brain network organization in schizophrenia.

  9. In vivo labeling of phencyclidine (PCP) receptors with 3H-TCP in the mouse brain

    International Nuclear Information System (INIS)

    Maurice, T.; Vignon, J.

    1990-01-01

    The phencyclidine (PCP) derivative N-[1-(2-thienyl)cyclohexyl]-piperidine (3H-TCP) was used to label in vivo the N-methyl-D-aspartate (NMDA) receptor-associated ionic channel in the mouse brain. After the injection of a tracer dose of 3H-TCP, a spread labeling throughout the brain was observed, but was the highest in the cerebellum. Preadministration of unlabeled TCP (30 mg/kg) resulted in a 90% reduction of 3H-TCP binding. PCP, TCP, MK-801, dexoxadrol, ketamine, and SKF 10,047 isomers dose-dependently prevented the in vivo 3H-TCP binding. ID50 determined in the cerebrum and the cerebellum were respectively correlated with K0.5 for 3H TCP high (rat cortex) and low affinity (rat cerebellum) sites in vitro. The pharmacological specificity of the 3H-TCP binding site in the cerebellum was significantly different from that in the cerebrum. ID50 values were generally higher than in the cerebrum and, particularly, MK-801, the most potent drug in the cerebrum, was without significant effect in the cerebellum, at any time and at doses as high as 30 mg/kg. N-[1-(2-benzo(b) thiophenyl)cyclohexyl]piperidine (BTCP), desipramine, and atropine showed a more efficient prevention of 3H-TCP binding in the cerebellum than in the cerebrum. The prevention of the binding by TCP or PCP, at doses close to their ID50 values, was rapid and then decreased slowly. The effect of MK-801 was long-lasting. This study confirm previous in vitro studies: 3H-TCP is an efficient tool for the labeling of the NMDA receptor-associated ionic channel

  10. Mineralocorticoid receptor blockade prevents stress-induced modulation of multiple memory systems in the human brain.

    Science.gov (United States)

    Schwabe, Lars; Tegenthoff, Martin; Höffken, Oliver; Wolf, Oliver T

    2013-12-01

    Accumulating evidence suggests that stress may orchestrate the engagement of multiple memory systems in the brain. In particular, stress is thought to favor dorsal striatum-dependent procedural over hippocampus-dependent declarative memory. However, the neuroendocrine mechanisms underlying these modulatory effects of stress remain elusive, especially in humans. Here, we targeted the role of the mineralocorticoid receptor (MR) in the stress-induced modulation of dorsal striatal and hippocampal memory systems in the human brain using a combination of event-related functional magnetic resonance imaging and pharmacologic blockade of the MR. Eighty healthy participants received the MR antagonist spironolactone (300 mg) or a placebo and underwent a stressor or control manipulation before they performed, in the scanner, a classification task that can be supported by the hippocampus and the dorsal striatum. Stress after placebo did not affect learning performance but reduced explicit task knowledge and led to a relative increase in the use of more procedural learning strategies. At the neural level, stress promoted striatum-based learning at the expense of hippocampus-based learning. Functional connectivity analyses showed that this shift was associated with altered coupling of the amygdala with the hippocampus and dorsal striatum. Mineralocorticoid receptor blockade before stress prevented the stress-induced shift toward dorsal striatal procedural learning, same as the stress-induced alterations of amygdala connectivity with hippocampus and dorsal striatum, but resulted in significantly impaired performance. Our findings indicate that the stress-induced shift from hippocampal to dorsal striatal memory systems is mediated by the amygdala, required to preserve performance after stress, and dependent on the MR. © 2013 Society of Biological Psychiatry.

  11. Size-exclusion chromatographic reconstitution of the bovine brain benzodiazepine receptor : Effects of lipid environment on the binding characteristics

    NARCIS (Netherlands)

    Viel, G.T; Yang, Q; Lundahl, P; Ensing, K; de Zeeuw, R.A

    1997-01-01

    The benzodiazepine receptor from calf brain was solubilized with sodium deoxycholate (2 mg/ml) in the presence of 0.5 M KCl and protease inhibitors, and bound flunitrazepam with an equilibrium dissociation constant (K-d) of 2.7+/-1.2 nM and with 0.40+/-0.04 pmol binding sites per mg protein (B-max).

  12. Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain

    DEFF Research Database (Denmark)

    Yang, Kai-Chun; Stepanov, Vladimir; Martinsson, Stefan

    2017-01-01

    Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the c...... sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain....

  13. Emotional eating is associated with increased brain responses to food-cues and reduced sensitivity to GLP-1 receptor activation

    NARCIS (Netherlands)

    van Bloemendaal, L.; Veltman, D.J.; ten Kulve, J.S.; Drent, M.L.; Barkhof, F.; Diamant, M.; IJzerman, R.G.

    2015-01-01

    Objective The neural correlates and pathophysiology of emotional eating are insufficiently known. Glucagon-like peptide-1 (GLP-1), a postprandial hormone, plays a role in feeding behavior by signaling satiety to the brain. GLP-1 receptor agonists, used for treatment of type 2 diabetes (T2DM),

  14. [STUDYING THE ROLE OF BRAIN MELANOCORTIN RECEPTORS IN THE SUPPRESSING OF FOOD INTAKE UNDER ETHER STRESS IN MICE].

    Science.gov (United States)

    Bazhan, N M; Kulikova, E V; Makarova, E N; Yakovleva, T V; Kazantseva, A Yu

    2015-12-01

    Melanocortin (MC) system regulates food intake under the rest conditions. Stress inhibits food intake. It is not clear whether brain MC system is involved in stress-induced anorexia in mice. The aim of the work was to investigate the effect of pharmacological blockade and activation of brain MC receptors on food intake under stress. C57B1/6J male mice were subjected to ether stress (0.5 minute ether anesthesia) before the administration of saline solution or synthetic non-selective blocker (SHU9119) or agonist (Melanotan II) of MC receptors into the lateral brain ventricle. Food intake was pre-stimulated with 17 hours of fasting in all mice. Ether stress decreased food intake, increased the plasma corticosterone level and hypothalamic mRNA AgRP (natural MC receptor antagonist) level at 1 hour after the stress. Pharmacological blockade of the MC receptors weakened stress-induced anorexia and decreased mRNA AgRP level in the hypothalamus. Pharmacological stimulation of the MC receptors enhanced ether stress-induced anorexia and hypercortisolism. Thus, our data demonstrated that the central MC system was involved in the development of stress-induced anorexia in mice.

  15. Cholecystokinin receptors: Biochemical demonstration and autoradiographical localization in rat brain and pancreas using [3H] cholecystokinin8 as radioligand

    International Nuclear Information System (INIS)

    Van Dijk, A.; Richards, J.G.; Trzeciak, A.; Gillessen, D.; Moehler, H.

    1984-01-01

    Since cholecystokinin8 (CCK8) seems to be the physiological ligand of CCK receptors in the brain, it would be the most suitable probe for the characterization of CCK receptors in radioligand binding studies. [ 3 H]CCK8 was synthetized with a specific radioactivity sufficient for the detection of high affinity binding sites. [ 3 H]CCK8 binds saturably and reversibly to distinct sites in rat brain and pancreas with nanomolar affinity. While the C-terminal tetrapeptide of CCK is the minimal structure required for nanomolar affinity in the brain, the entire octapeptide sequence is required for binding affinity in pancreas. Desulfated CCK8 and several gastrin-I peptides, which are likewise unsulfated, show virtually no affinity to the binding sites in pancreas but high affinity in cerebral cortex. The ligand specificity of the CCK peptides corresponds to their electrophysiological potency in the brain and their stimulation of secretion in pancreas, respectively. Autoradiographically, high densities of [ 3 H]CCK8 binding sites were found in cerebral cortex and olfactory bulb, medium levels in nucleus accumbens, hippocampus, dentate gyrus, and striatum with virtually no labeling in cerebellum. This pattern is similar to the distribution of CCK-like immunoreactivity in the brain. In pancreas, equally high levels of [ 3 H]CCK8 labeling were found in the exocrine and endocrine region. [ 3 H]CCK8 binding sites differ from those identified previously with [ 125 I]Bolton-Hunter-CCK33 by their sensitivity to guanyl nucleotides in the brain, their ion dependency in the brain, and pancreas, and their different autoradiographical localization in some parts of the brain. The distribution of CCK binding sites labeled with [ 3 H]CCK8 appears to correlate better with the CCK immunoreactivity than those labeled with [ 125 I]Bolton-Hunter-CCK33. Thus, [ 3 H]CCK8 appears to be the radioligand of choice for the investigation of CCK receptors

  16. Peripheral benzodiazepines receptor (PBR stimulates steroidogenesis: A potential neuroprotective pathway following brain damage

    Directory of Open Access Journals (Sweden)

    George E. Barreto

    2015-04-01

    Full Text Available The effects of neuroactive steroids have been highly assessed for their significance on inflammation resolution induced by cytotoxic agents. Steroids are derived from cholesterol, and this regulatory pathway may be a target for possible protective strategies. For example, the increased expression of peripheral benzodiazepine receptor (PBR stimulates steroids production, and the action of specific ligands on PBR favors the reduction of glial activity and act as a protective mechanism. The augmented expression of PBR and steroidogenic acute regulatory protein (StAR after injury is associated with local production of steroids by glial cells. For instance, cholesterol is captured by StAR in the outer mitochondrial membrane that transfers it to PBR, which uses it as substrate for the enzyme P450scc in the inner mitochondrial membrane. Some ligands, such as 4'-Chlorodiazepam (Ro5-4864 and isoquinoline carboxamide (PK 11195, act as agonists of the PBR receptor. Previous studies indicate that Ro5-4864 reduces neuronal loss, thus implying the regulation of mitochondrial transition after a traumatic brain injury. In this work, we assess the effects of PBR ligands directly involved in neuronal cell survival and proliferation after injury, thereby activating potential downstream targets as novel therapeutic approaches.

  17. [3H]opipramol labels a novel binding site and sigma receptors in rat brain membranes

    International Nuclear Information System (INIS)

    Ferris, C.D.; Hirsch, D.J.; Brooks, B.P.; Snowman, A.M.; Snyder, S.H.

    1991-01-01

    Opipramol (OP), a clinically effective antidepressant with a tricyclic structure, is inactive as an inhibitor of biogenic amine uptake. [ 3 H]Opipramol binds saturably to rat brain membranes (apparent KD = 4 nM, Bmax = 3 pmol/mg of protein). [ 3 H]Opipramol binding can be differentiated into haloperidol-sensitive and -resistant components, with Ki values for haloperidol of 1 nM (Bmax = 1 pmol/mg of protein) and 350 nM (Bmax = 1.9 pmol/mg of protein), respectively. The drug specificity of the haloperidol-sensitive component is the same as that of sigma receptors labeled with (+)-[ 3 H]3-(3-hydroxyphenyl)-N-(1-propyl)piperdine. The haloperidol-resistant component does not correspond to any known neurotransmitter receptor or uptake recognition site. It displays high affinity for phenothiazines and related structures such as perphenazine, clopenthixol, and flupenthixol, whose potencies are comparable to that of opipramol. Because certain of these drugs are more potent at the haloperidol-resistant opipramol site than in exerting any other action, it is possible that this opipramol-selective site may mediate their therapeutic effects

  18. Aluminum access to the brain: A role for transferrin and its receptor

    International Nuclear Information System (INIS)

    Roskams, A.J.; Connor, J.R.

    1990-01-01

    The toxicity of aluminum in plant and animal cell biology is well established, although poorly understood. Several recent studies have identified aluminum as a potential, although highly controversial, contributory factor in the pathology of Alzheimer's disease, amyotrophic lateral sclerosis, and dialysis dementia. For example, aluminum has been found in high concentrations in senile plaques and neurofibrillary tangles, which occur in the brains of subjects with Alzheimer's disease. However, a mechanism for the entry of aluminum (Al 3+ ) into the cells of the central nervous system (CNS) has yet to be found. Here the authors describe a possible route of entry for aluminum into the cells of the CNS via the same high-affinity receptor-ligand system that has been postulated for iron (Fe 3 ) aluminum is able to gain access to the central nervous system under normal physiological conditions. Furthermore, these data suggest that the interaction between transferrin and its receptor may function as a general metal ion regulatory system in the CNS, extending beyond its postulated role in iron regulation

  19. Cholecystokinin-8 suppressed /sup 3/H-etorphine binding to rat brain opiate receptors

    Energy Technology Data Exchange (ETDEWEB)

    Wang, X.J.; Fan, S.G.; Ren, M.F.; Han, J.S.

    1989-01-01

    Radioreceptor assay (RRA) was adopted to analyze the influence of CCK-8 on /sup 3/H-etorphine binding to opiate receptors in rat brain synaptosomal membranes (P2). In the competition experiment CCK-8 suppressed the binding of /sup 3/H-etorphine. This effect was completely reversed by proglumide at 1/mu/M. Rosenthal analysis for saturation revealed two populations of /sup 3/H-etorphine binding sites. CCK-8 inhibited /sup 3/H-etorphine binding to the high affinity sites by an increase in Kd and decrease in Bmax without significant changes in the Kd and Bmax of the low affinity sites. This effect of CCK-8 was also completely reversed by proglumide at 1/mu/M. Unsulfated CCK-8 produced only a slight increase in Kd of the high affinity sites without affecting Bmax. The results suggest that CCK-8 might be capable of suppressing the high affinity opioid binding sites via the activation of CCK receptor.

  20. Characterization of the Distance Relationship Between Localized Serotonin Receptors and Glia Cells on Fluorescence Microscopy Images of Brain Tissue.

    Science.gov (United States)

    Jacak, Jaroslaw; Schaller, Susanne; Borgmann, Daniela; Winkler, Stephan M

    2015-08-01

    We here present two new methods for the characterization of fluorescent localization microscopy images obtained from immunostained brain tissue sections. Direct stochastic optical reconstruction microscopy images of 5-HT1A serotonin receptors and glial fibrillary acidic proteins in healthy cryopreserved brain tissues are analyzed. In detail, we here present two image processing methods for characterizing differences in receptor distribution on glial cells and their distribution on neural cells: One variant relies on skeleton extraction and adaptive thresholding, the other on k-means based discrete layer segmentation. Experimental results show that both methods can be applied for distinguishing classes of images with respect to serotonin receptor distribution. Quantification of nanoscopic changes in relative protein expression on particular cell types can be used to analyze degeneration in tissues caused by diseases or medical treatment.

  1. Assessment of dopamine receptor blockade by neuroleptic drugs in the living human brain

    International Nuclear Information System (INIS)

    Wong, D.F.; Wagner, H.N. Jr.; Coyle, J.

    1985-01-01

    Positron emission tomography (PET) makes it possible to attempt to relate directly the antipsychotic effect of neuroleptic drugs and their blocking effect on dopamine receptors (D2) in vivo. The authors have examined the ability of haloperidol (HAL) and molindone (MOL) to block the binding of C-11 n-methylspiperone (NMSP) in 6 normal subjects. A dose of 0.05 mg/kg of HAL resulted in a 68% drop in the slope of the caudate/cerebellum (Ca/Cb) vs. time. This slope is related to the rate of specific binding of NMSP to the receptor. A dose response was seen with both drugs. With increasing doses of HAL from .05 to 0.082 mg/kg, CA/Cb vs. time slope fell from .235 to .156/min. (N=4), progressively. Similarly with increasing doses of MOL of .16-.44 mg/kg slopes decreased from .0335 to .0155/min. (N=4). Similar degrees of post injection Ca/Cb ratio were produced with quantities of MOL and HAL administered in the oral dose ratio of doses 3-5:1 times greater than HAL. This is also the dose ratio at which we found similar dopamine receptor blockade by PET in vivo. A question that arises is why the in vitro affinity of HAL for D2 is 30 times greater than that of MOL in the human brain. The results raise the possibility that MOL metabolites are not only active in blocking D2 but indeed may possibly be more potent than MOL itself. It also helps confirm the site of action of MOL and its in vivo metabolites

  2. G-protein-coupled estrogen receptor 1 is involved in brain development during zebrafish (Danio rerio) embryogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Yanan; Liu, Xiaochun [State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275 (China); Zhu, Pei; Li, Jianzhen; Sham, Kathy W.Y. [School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong (China); Cheng, Shuk Han [Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong (China); Li, Shuisheng; Zhang, Yong [State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275 (China); Cheng, Christopher H.K., E-mail: chkcheng@cuhk.edu.hk [School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong (China); Lin, Haoran, E-mail: lsslhr@mail.sysu.edu.cn [State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275 (China); College of Ocean, Hainan University, Haikou 570228, Hainan (China)

    2013-05-24

    Highlights: •The Gper expression was detected in the developing brain of zebrafish. •Gper morpholino knockdown induced apoptosis of brain cells. •Gper morpholino knockdown reduced expression in neuron markers. •Zebrafish Gper may be involved in neuronal development. -- Abstract: G-protein-coupled estrogen receptor 1 (Gper, formerly known as GPR30) is found to be a trophic and protective factor in mediating action of estrogen in adult brain, while its role in developing brain remains to be elucidated. Here we present the expression pattern of Gper and its functions during embryogenesis in zebrafish. Both the mRNA and protein of Gper were detected throughout embryogenesis. Whole mount in situ hybridization (WISH) revealed a wide distribution of gper mRNAs in various regions of the developing brain. Gper knockdown by specific morpholinos resulted in growth retardation in embryos and morphological defects in the developing brain. In addition, induced apoptosis, decreased proliferation of the brain cells and maldevelopment of sensory and motor neurons were also found in the morphants. Our results provide novel insights into Gper functions in the developing brain, revealing that Gper can maintain the survival of the brain cells, and formation and/or differentiation of the sensory and motor neurons.

  3. G-protein-coupled estrogen receptor 1 is involved in brain development during zebrafish (Danio rerio) embryogenesis

    International Nuclear Information System (INIS)

    Shi, Yanan; Liu, Xiaochun; Zhu, Pei; Li, Jianzhen; Sham, Kathy W.Y.; Cheng, Shuk Han; Li, Shuisheng; Zhang, Yong; Cheng, Christopher H.K.; Lin, Haoran

    2013-01-01

    Highlights: •The Gper expression was detected in the developing brain of zebrafish. •Gper morpholino knockdown induced apoptosis of brain cells. •Gper morpholino knockdown reduced expression in neuron markers. •Zebrafish Gper may be involved in neuronal development. -- Abstract: G-protein-coupled estrogen receptor 1 (Gper, formerly known as GPR30) is found to be a trophic and protective factor in mediating action of estrogen in adult brain, while its role in developing brain remains to be elucidated. Here we present the expression pattern of Gper and its functions during embryogenesis in zebrafish. Both the mRNA and protein of Gper were detected throughout embryogenesis. Whole mount in situ hybridization (WISH) revealed a wide distribution of gper mRNAs in various regions of the developing brain. Gper knockdown by specific morpholinos resulted in growth retardation in embryos and morphological defects in the developing brain. In addition, induced apoptosis, decreased proliferation of the brain cells and maldevelopment of sensory and motor neurons were also found in the morphants. Our results provide novel insights into Gper functions in the developing brain, revealing that Gper can maintain the survival of the brain cells, and formation and/or differentiation of the sensory and motor neurons

  4. Neuronal Culture and labelling of receptors of rat brain by a radioactive molecule labelled with technetium

    International Nuclear Information System (INIS)

    Barhoumi, C; Mejri, N.; Saidi, M.; Coulais, Y.; Dunia, D.; Masmoudi, O.; Amri, M.

    2009-01-01

    Alzheimer's disease is a neurodegenerative disease of the brain which causes progressive and irreversible loss of mental function. It is characterized by a decrease of serotoninergic neurons that carry the 5HT1A receptors. In our study, we performed cultures of hippocampal and cortical neurons from brains of young rats. After the differentiation of these neurons, some wells of cell culture were incubated with 8 OH DPAT, a 5HT1A agonist of serotonin, which are located on the surface of neurons.The neurons were then incubated with a molecule labelled with technetium 99m Tc. These neurons are lysed and the radioactivity is read. The results show that for the culture of neurons in the hippocampus, we have levels of radioactivity of cells treated with agonist, below the level of radioactivity of cells treated with the radioactive molecule. Cortical neurons show the same level of radioactivity of cells treated with agonist and for cells treated only with the labelled molecule. Our results show a decrease in the fixation of the labelled molecule on serotoninergic neurons in the hippocampus compared to neurons in the cortex. This work will be continued in humans in order to achieve early diagnosis of Alzheimer's disease

  5. Localization of glucocorticoid receptor mRNA in the male rat brain by in situ hybridization

    International Nuclear Information System (INIS)

    Aronsson, M.; Fuxe, K.; Dong, Y.; Agnati, L.F.; Okret, S.; Gustafsson, J.A.

    1988-01-01

    The localization and distribution of mRNA encoding the glucocorticoid receptor (GR) was investigated in tissue sections of the adult male rat brain by in situ hybridization and RNA blot analysis. GR mRNA levels were measured by quantitative autoradiography with 35S- and 32P-labeled RNA probes, respectively. Strong labeling was observed within the pyramidal nerve cells of the CA1 and CA2 areas of the hippocampal formation, in the granular cells of the dentate gyrus, in the parvocellular nerve cells of the paraventricular hypothalamic nucleus, and in the cells of the arcuate nucleus, especially the parvocellular part. Moderate labeling of a large number of nerve cells was observed within layers II, III, and VI of the neocortex and in many thalamic nuclei, especially the anterior and ventral nuclear groups as well as several midline nuclei. Within the cerebellar cortex, strong labeling was observed all over the granular layer. In the lower brainstem, strong labeling was found within the entire locus coeruleus and within the mesencephalic raphe nuclei rich in noradrenaline and 5-hydroxytryptamine cell bodies, respectively. A close correlation was found between the distribution of GR mRNA and the distribution of previously described GR immunoreactivity. These studies open the possibility of obtaining additional information on in vivo regulation of GR synthesis and how the brain may alter its sensitivity to circulating glucocorticoids

  6. The Vitamin D Receptor (VDR Gene Polymorphisms in Turkish Brain Cancer Patients

    Directory of Open Access Journals (Sweden)

    Bahar Toptaş

    2013-01-01

    Full Text Available Objective. It has been stated that brain cancers are an increasingly serious issue in many parts of the world. The aim of our study was to determine a possible relationship between Vitamin D receptor (VDR gene polymorphisms and the risk of glioma and meningioma. Methods. We investigated the VDR Taq-I and VDR Fok-I gene polymorphisms in 100 brain cancer patients (including 44 meningioma cases and 56 glioma cases and 122 age-matched healthy control subjects. This study was performed by polymerase chain reaction-based restriction fragment length polymorphism (RF LP. Results. VDR Fok-I ff genotype was significantly increased in meningioma patients (15.9% compared with controls (2.5%, and carriers of Fok-I ff genotype had a 6.47-fold increased risk for meningioma cases. There was no significant difference between patients and controls for VDR Taq-I genotypes and alleles. Conclusions. We suggest that VDR Fok-I genotypes might affect the development of meningioma.

  7. High-affinity cannabinoid binding site in brain: A possible marijuana receptor

    International Nuclear Information System (INIS)

    Nye, J.S.

    1988-01-01

    The mechanism by which delta 9 tetrahydrocannabinol (delta 9 THC), the major psychoactive component of marijuana or hashish, produces its potent psychological and physiological effects is unknown. To find receptor binding sites for THC, we designed a water-soluble analog for use as a radioligand. 5'-Trimethylammonium-delta 8 THC (TMA) is a positively charged analog of delta- 8 THC modified on the 5' carbon, a portion of the molecule not important for its psychoactivity. We have studied the binding of [ 3 H]-5'-trimethylammonium-delta- 8 THC ([ 3 H]TMA) to rat neuronal membranes. [ 3 H]TMA binds saturably and reversibly to brain membranes with high affinity to apparently one class of sites. Highest binding site density occurs in brain, but several peripheral organs also display specific binding. Detergent solubilizes the sites without affecting their pharmacologial properties. Molecular sieve chromatography reveals a bimodal peak of [ 3 H]TMA binding activity of approximately 60,000 daltons apparent molecular weight

  8. Peripheral benzodiazepine receptors in the brain of cirrhosis patients with manifest hepatic encephalopathy

    Energy Technology Data Exchange (ETDEWEB)

    Iversen, Peter; Bender, Dirk; Munk, Ole L.; Cumming, Paul [Aarhus University Hospital, PET Centre, Aarhus (Denmark); Aagaard Hansen, Dorthe; Keiding, Susanne [Aarhus University Hospital, PET Centre, Aarhus (Denmark); Aarhus University Hospital, Department of Medicine V (Hepatology), Aarhus (Denmark); Rodell, Anders [Aarhus University Hospital, Centre of Functionally Integrative Neuroscience (CFIN), Aarhus (Denmark)

    2006-07-15

    It has been suggested that ammonia-induced enhancement of peripheral benzodiazepine receptors (PBRs) in the brain is involved in the development of hepatic encephalopathy (HE). This hypothesis is based on animal experiments and studies of post-mortem human brains using radiolabelled PK11195, a specific ligand for PBR, but to our knowledge has not been tested in living patients. The aim of the present study was to test this hypothesis by measuring the number of cerebral PBRs in specific brain regions in cirrhotic patients with an acute episode of clinically manifest HE and healthy subjects using dynamic {sup 11}C-PK11195 brain PET. Eight cirrhotic patients with an acute episode of clinically manifest HE (mean arterial ammonia 81 {mu}mol/l) and five healthy subjects (22 {mu}mol/l) underwent dynamic {sup 11}C-PK11195 and {sup 15}O-H{sub 2}O PET, co-registered with MR images. Brain regions (putamen, cerebellum, cortex and thalamus) were delineated on co-registered {sup 15}O-H{sub 2} {sup 15}O and MR images and copied to the dynamic {sup 15}O-H{sub 2}O and {sup 11}C-PK11195 images. Regional cerebral blood flow (CBF) ({sup 15}O-H{sub 2}O scan) and the volume of distribution of PK11195 ({sup 11}C-PK11195 scan) were calculated by kinetic analysis. There were regional differences in the CBF, with lowest values in the cortex and highest values in the putamen in both groups of subjects (p<0.05), but no significant differences between the groups. There were no significant differences in the volume of distribution of PK11195 (V{sub d}) between regions or between the two groups of subjects. Mean values of V{sub d} ranged from 1.0 to 1.1 in both groups of subjects. The results do not confirm the hypothesis of an increased number of PBRs in patients with HE. (orig.)

  9. A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury.

    Science.gov (United States)

    Delbary-Gossart, Sandrine; Lee, Sangmi; Baroni, Marco; Lamarche, Isabelle; Arnone, Michele; Canolle, Benoit; Lin, Amity; Sacramento, Jeffrey; Salegio, Ernesto A; Castel, Marie-Noelle; Delesque-Touchard, Nathalie; Alam, Antoine; Laboudie, Patricia; Ferzaz, Badia; Savi, Pierre; Herbert, Jean-Marc; Manley, Geoffrey T; Ferguson, Adam R; Bresnahan, Jacqueline C; Bono, Françoise; Beattie, Michael S

    2016-06-01

    The p75 neurotrophin receptor is important in multiple physiological actions including neuronal survival and neurite outgrowth during development, and after central nervous system injury. We have discovered a novel piperazine-derived compound, EVT901, which interferes with p75 neurotrophin receptor oligomerization through direct interaction with the first cysteine-rich domain of the extracellular region. Using ligand binding assays with cysteine-rich domains-fused p75 neurotrophin receptor, we confirmed that EVT901 interferes with oligomerization of full-length p75 neurotrophin receptor in a dose-dependent manner. Here we report that EVT901 reduces binding of pro-nerve growth factor to p75 neurotrophin receptor, blocks pro-nerve growth factor induced apoptosis in cells expressing p75 neurotrophin receptor, and enhances neurite outgrowth in vitro Furthermore, we demonstrate that EVT901 abrogates p75 neurotrophin receptor signalling by other ligands, such as prion peptide and amyloid-β. To test the efficacy of EVT901 in vivo, we evaluated the outcome in two models of traumatic brain injury. We generated controlled cortical impacts in adult rats. Using unbiased stereological analysis, we found that EVT901 delivered intravenously daily for 1 week after injury, reduced lesion size, protected cortical neurons and oligodendrocytes, and had a positive effect on neurological function. After lateral fluid percussion injury in adult rats, oral treatment with EVT901 reduced neuronal death in the hippocampus and thalamus, reduced long-term cognitive deficits, and reduced the occurrence of post-traumatic seizure activity. Together, these studies provide a new reagent for altering p75 neurotrophin receptor actions after injury and suggest that EVT901 may be useful in treatment of central nervous system trauma and other neurological disorders where p75 neurotrophin receptor signalling is affected. © The Author (2016). Published by Oxford University Press on behalf of the

  10. Selective labelling of 5-HT{sub 7} receptor recognition sites in rat brain using [{sup 3}H]5-carboxamidotryptamine

    Energy Technology Data Exchange (ETDEWEB)

    Stowe, R.L.; Barnes, N.M. [Department of Pharmacology, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT (United Kingdom)

    1998-12-01

    The aim of the present study was to establish a radioligand binding assay to selectively label the native 5-HT{sub 7} receptor expressed in rat brain. In rat whole brain (minus cerebellum and striatum) homogenate, ({+-})-pindolol (10 {mu}M)-insensitive [{sup 3}H]5-CT ([{sup 3}H]5-carboxamidotryptamine; 0.5 nM) specific binding (defined by 5-HT, 10 {mu}M) displayed a pharmacological profile similar to the recombinant 5-HT{sub 7} receptor, although the Hill coefficients for competition curves generated by methiothepin, ritanserin, sumatriptan, clozapine and pimozide were significantly less than unity. In homogenates of rat hypothalamus, ({+-})-pindolol (10 {mu}M)-insensitive [{sup 3}H]5-CT recognition sites also resembled, pharmacologically, the 5-HT{sub 7} receptor, although pimozide still generated Hill coefficients significantly less than unity. Subsequent studies were performed in the additional presence of WAY100635 (100 nM) to prevent [{sup 3}H]5-CT binding to residual, possibly, 5-HT{sub 1A} sites. Competition for this [{sup 3}H]5-CT binding indicated the labelling in whole rat brain homogenate of a homogenous population of sites with the pharmacological profile of the 5-HT{sub 7} receptor. Saturation studies also indicated that ({+-})-pindolol (10 {mu}M)/WAY 100635 (100 nM)-insensitive [{sup 3}H]5-CT binding to homogenates of whole rat brain was saturable and to an apparently homogenous population of sites which were labelled with nanomolar affinity (B{sub max}=33.2{+-}0.7 fmol mg{sup -1} protein, pK{sub d}=8.78{+-}0.05, mean{+-}S.E.M., n=3). The development of this 5-HT{sub 7} receptor binding assay will aid investigation of the rat native 5-HT{sub 7} receptor. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  11. Selective labelling of 5-HT7 receptor recognition sites in rat brain using [3H]5-carboxamidotryptamine

    International Nuclear Information System (INIS)

    Stowe, R.L.; Barnes, N.M.

    1998-01-01

    The aim of the present study was to establish a radioligand binding assay to selectively label the native 5-HT 7 receptor expressed in rat brain. In rat whole brain (minus cerebellum and striatum) homogenate, (±)-pindolol (10 μM)-insensitive [ 3 H]5-CT ([ 3 H]5-carboxamidotryptamine; 0.5 nM) specific binding (defined by 5-HT, 10 μM) displayed a pharmacological profile similar to the recombinant 5-HT 7 receptor, although the Hill coefficients for competition curves generated by methiothepin, ritanserin, sumatriptan, clozapine and pimozide were significantly less than unity. In homogenates of rat hypothalamus, (±)-pindolol (10 μM)-insensitive [ 3 H]5-CT recognition sites also resembled, pharmacologically, the 5-HT 7 receptor, although pimozide still generated Hill coefficients significantly less than unity. Subsequent studies were performed in the additional presence of WAY100635 (100 nM) to prevent [ 3 H]5-CT binding to residual, possibly, 5-HT 1A sites. Competition for this [ 3 H]5-CT binding indicated the labelling in whole rat brain homogenate of a homogenous population of sites with the pharmacological profile of the 5-HT 7 receptor. Saturation studies also indicated that (±)-pindolol (10 μM)/WAY 100635 (100 nM)-insensitive [ 3 H]5-CT binding to homogenates of whole rat brain was saturable and to an apparently homogenous population of sites which were labelled with nanomolar affinity (B max =33.2±0.7 fmol mg -1 protein, pK d =8.78±0.05, mean±S.E.M., n=3). The development of this 5-HT 7 receptor binding assay will aid investigation of the rat native 5-HT 7 receptor. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  12. Characterization of cholinergic muscarinic receptor-stimulated phosphoinositide metabolism in brain from immature rats

    International Nuclear Information System (INIS)

    Balduini, W.; Murphy, S.D.; Costa, L.G.

    1990-01-01

    Hydrolysis of phosphoinositides elicited by stimulation of cholinergic muscarinic receptors has been studied in brain from neonatal (7-day-old) rats in order to determine: (1) whether the neonatal rat could provide a good model system to study this signal-transduction pathway; and (2) whether potential differences with adult nerve tissue would explain the differential, age-related effects of cholinergic agonists. Accumulation of [3H] inositol phosphates in [3H]inositol prelabeled slices from neonatal and adult rats was measured as an index of phosphoinositide metabolism. Full (acetylcholine, methacholine, carbachol) and partial (oxotremorine, bethanechol) agonists had qualitatively similar, albeit quantitatively different, effects in neonatal and adult rats. Atropine and pirenzepine effectively blocked the carbachol-induced response with inhibition constants of 1.2 and 20.7 nM, respectively. In all brain areas, response to all agonists was higher in neonatal than adult rats, and in hippocampus and cerebral cortex the response was higher than in cerebellum or brainstem. The relative intrinsic activity of partial agonists was higher in the latter two areas (0.6-0.7) than in the former two (0.3-0.4). Carbachol-stimulated phosphoinositide metabolism in brain areas correlated well with the binding of [3H]QNB (r2 = 0.627) and, particularly, with [3H]pirenzepine (r2 = 0.911). In cerebral cortex the effect of carbachol was additive to that of norepinephrine and glutamate. The presence of calcium (250-500 microM) was necessary for maximal response to carbachol to be elicited; the EC50 value for Ca2+ was 65.4 microM. Addition of EDTA completely abolished the response. Removal of sodium ions from the incubation medium reduced the response to carbachol by 50%

  13. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs.

    Science.gov (United States)

    Eigenmann, Daniela Elisabeth; Dürig, Carmen; Jähne, Evelyn Andrea; Smieško, Martin; Culot, Maxime; Gosselet, Fabien; Cecchelli, Romeo; Helms, Hans Christian Cederberg; Brodin, Birger; Wimmer, Laurin; Mihovilovic, Marko D; Hamburger, Matthias; Oufir, Mouhssin

    2016-06-01

    The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Change in the properties of the opiate receptors of the brain under conditions of habituation of rats to morphine

    International Nuclear Information System (INIS)

    Zaitsev, S.V.; Sergeeva, M.G.; Chichenkov, O.N.; Petrov, V.E.; Varfolomeev, S.D.

    1987-01-01

    The influence of prolonged administration of morphine on the properties of the opiate receptors of the rat brain was investigated. For this purpose they conducted an analysis of the isotherms of binding of labeled μ-, σ-, and chi-ligands: morphine, D-Ala 2 , D-Leu 5 -enkephalin, and ethylketocyclazocin, with membrane preparations of the brains of rats tolerant to morphine, as well as the control animals. For a quantitative determination of the dissociation constants of the ligand-receptor complexes (K) and the concentration of the reagents ([Q]), they used differential method and the method of simulation modeling. It was shown that the values of K and [Q] for individual animals are subjected to substantial dispersion, whereas the ratios [Q]/K undergo minor individual fluctuations, both in the control group and in the group of rats tolerant to morphine. This permits the ratio [Q]/K to be singled out as one of the main parameters for comparing the properties of opiate receptors of various groups of animals. Using this criterion, as well as the method of simulated modeling, it was shown that the development of tolerance is accompanied by a change in the properties of the δ-receptors (the ratio [Q]/K decreases by a factor of more than two). In contrast to the δ-receptors, no significant influence of the tolerance on the properties of the μ- and chi-receptors, as well as the ultrahigh-affinity ligand binding sites, was detected

  15. Change in the properties of the opiate receptors of the brain under conditions of habituation of rats to morphine

    Energy Technology Data Exchange (ETDEWEB)

    Zaitsev, S.V.; Sergeeva, M.G.; Chichenkov, O.N.; Petrov, V.E.; Varfolomeev, S.D.

    1987-02-20

    The influence of prolonged administration of morphine on the properties of the opiate receptors of the rat brain was investigated. For this purpose they conducted an analysis of the isotherms of binding of labeled ..mu..-, sigma-, and chi-ligands: morphine, D-Ala/sup 2/, D-Leu/sup 5/-enkephalin, and ethylketocyclazocin, with membrane preparations of the brains of rats tolerant to morphine, as well as the control animals. For a quantitative determination of the dissociation constants of the ligand-receptor complexes (K) and the concentration of the reagents ((Q)), they used differential method and the method of simulation modeling. It was shown that the values of K and (Q) for individual animals are subjected to substantial dispersion, whereas the ratios (Q)/K undergo minor individual fluctuations, both in the control group and in the group of rats tolerant to morphine. This permits the ratio (Q)/K to be singled out as one of the main parameters for comparing the properties of opiate receptors of various groups of animals. Using this criterion, as well as the method of simulated modeling, it was shown that the development of tolerance is accompanied by a change in the properties of the delta-receptors (the ratio (Q)/K decreases by a factor of more than two). In contrast to the delta-receptors, no significant influence of the tolerance on the properties of the ..mu..- and chi-receptors, as well as the ultrahigh-affinity ligand binding sites, was detected.

  16. Hydrolysis of lipoproteins by sPLA2's enhances mitogenesis and eicosanoid release from vascular smooth muscle cells: Diverse activity of sPLA2's IIA, V and X.

    Science.gov (United States)

    Pruzanski, Waldemar; Kopilov, Julia; Kuksis, Arnis

    2016-01-01

    Mitogenesis of Vascular Smooth Muscle Cells (VSMC) plays an important role in atherogenesis. Until recently, the effect of lipid subfractions has not been clarified. Secretory phospholipases A2 (sPLA2's) hydrolyse glycerophospholipids and release pro-inflammatory lyso-lipids, oxidized and non-oxidized fatty acids and isoprostanes. They localize in the vascular wall. We hypothesized that structurally similar sPLA2's may exert different impact on VSMC. The influence of sPLA2's, IIA, V, X, HDL, LDL, and hydrolysis products was tested on mitogenesis of VSMC, i.e., the early effect on the cell membrane phospholipids, and on PGE2 and LTB4 release, i.e., late effect of Cyclooxygenase and 5-lipooxygenase activity in VSMC. Mitogenesis was significantly enhanced by HDL and LDL, and by products of sPLA2 hydrolysis. Hydrolysis of HDL or LDL enhanced mitogenic activity in order V>X>IIA. The release of PGE2 was enhanced by group X sPLA2 and by HDL hydrolyzed by groups V and X. LDL and its hydrolysis products enhanced the release of PGE2 in order X>V>IIA. The release of LTB4 was markedly increased by LDL and HDL, and by hydrolytic products of group V and X, but not group IIA sPLA2. Our study demonstrates a diverse interaction of pro-inflammatory sPLA2's with HDL and LDL affecting both mitogenesis and eicosanoid release from VSMC, therefore potentially enhancing their pro-atherogenic activity. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. In vivo imaging of brain estrogen receptors in rats : a 16α-18F-fluoro-17β-estradiol PET study

    NARCIS (Netherlands)

    Khayum, Mohammed A; de Vries, Erik F J; Glaudemans, Andor W J M; Dierckx, Rudi A J O; Doorduin, Janine

    UNLABELLED: The steroid hormone estrogen is important for brain functioning and is thought to be involved in brain diseases, such as Alzheimer disease and depression. The action of estrogen is mediated by estrogen receptors (ERs). To understand the role of estrogens in brain functioning, it is

  18. Effect of paraoxon on muscarinic, dopamine and γ-aminobutyric acid receptors of brain and sensitivity to muscarinic antagonists

    International Nuclear Information System (INIS)

    Fernando, J.C.R.; Hoskins, B.; Ho, I.K.

    1986-01-01

    Several acetylcholinesterase (AChE) inhibitors decrease muscarinic cholinergic (mACh) receptors in the brain, alteration of dopamine (DA) and γ-aminobutyric acid (GABA) receptors after AChE inhibition was also reported. In view of the important interactions among DA, GABA and ACh systems, whether this is a common effect of AChE inhibitors should be established. They report the effect of the AChE inhibitor, paraoxon, on DA, GABA and mACh receptors in the rat. The binding of 3 H-QNB (for mACh), 3 H-spiperone (for DA) and 3 H-muscimol (for GABA) to striatal and hippocampal membranes was analyzed. Also, behavioral sensitivity to atropine was studied. Twenty-four hr after a single dose (0.75 mg/kg, s.c.) of paraoxon, the density of mACh receptors in the striatum was decreased but, at 3 days, no change was seen. In the hippocampus, the mACh receptors were not affected. Repeated treatment with paraoxon (0.3 mg/kg, 48 hourly) for 2 weeks reduced the mACh receptor density in both regions. Neither single nor repeated paraoxon treatment had an effect on DA or GABA receptors. After single or repeated dosing with paraoxon, myoclonus induced by atropine (10 mg/kg, i.p.) was enhanced. The results show rapid downregulation of mACh receptors by paraoxon. DA or GABA, however, appear not to be affected under these treatment regimens

  19. Developmental aspects of the rat brain insulin receptor: loss of sialic acid and fluctuation in number characterize fetal development

    International Nuclear Information System (INIS)

    Brennan, W.A. Jr.

    1988-01-01

    In this study, I have investigated the structure of the rat brain insulin receptor during fetal development. There is a progressive decrease in the apparent molecular size of the brain alpha-subunit during development: 130K on day 16 of gestation, 126K at birth, and 120K in the adult. Glycosylation was investigated as a possible reason for the observed differences in the alpha-subunit molecular size. The results show that the developmental decrease in the brain alpha-subunit apparent molecular size is due to a parallel decrease in sialic acid content. This was further confirmed by measuring the retention of autophosphorylated insulin receptors on wheat germ agglutinin (WGA)-Sepharose. An inverse correlation between developmental age and retention of 32 P-labeled insulin receptors on the lectin column was observed. Insulin binding increases 6-fold between 16 and 20 days of gestation [61 +/- 25 (+/- SE) fmol/mg protein and 364 +/- 42 fmol/mg, respectively]. Thereafter, binding in brain membranes decreases to 150 +/- 20 fmol/mg by 2 days after birth, then reaches the adult level of 63 +/- 15 fmol/mg. In addition, the degree of insulin-stimulated autophosphorylation closely parallels the developmental changes in insulin binding. Between 16 and 20 days of fetal life, insulin-stimulated phosphorylation of the beta-subunit increases 6-fold. Thereafter, the extent of phosphorylation decreases rapidly, reaching adult values identical with those in 16-day-old fetal brain. These results suggest that the embryonic brain possesses competent insulin receptors whose expression changes markedly during fetal development. This information should be important in defining the role of insulin in the developing nervous system

  20. Amelioration of cold injury-induced cortical brain edema formation by selective endothelin ETB receptor antagonists in mice.

    Science.gov (United States)

    Michinaga, Shotaro; Nagase, Marina; Matsuyama, Emi; Yamanaka, Daisuke; Seno, Naoki; Fuka, Mayu; Yamamoto, Yui; Koyama, Yutaka

    2014-01-01

    Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice). Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV) administration of BQ788 (ETB antagonist), IRL-2500 (ETB antagonist), or FR139317 (ETA antagonist) prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults.

  1. Amelioration of cold injury-induced cortical brain edema formation by selective endothelin ETB receptor antagonists in mice.

    Directory of Open Access Journals (Sweden)

    Shotaro Michinaga

    Full Text Available Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice. Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV administration of BQ788 (ETB antagonist, IRL-2500 (ETB antagonist, or FR139317 (ETA antagonist prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults.

  2. Gastrin-releasing peptide receptors in the central nervous system: role in brain function and as a drug target

    Directory of Open Access Journals (Sweden)

    Rafael eRoesler

    2012-12-01

    Full Text Available Neuropeptides acting on specific cell membrane receptors of the G protein-coupled receptor (GPCR superfamily regulate a range of important aspects of nervous and neuroendocrine function. Gastrin-releasing peptide (GRP is a mammalian neuropeptide that binds to the GRP receptor (GRPR, BB2. Increasing evidence indicates that GRPR-mediated signaling in the central nervous system (CNS plays an important role in regulating brain function, including aspects related to emotional responses, social interaction, memory, and feeding behavior. In addition, some alterations in GRP or GRPR expression or function have been described in patients with neurodegenerative, neurodevelopmental, and psychiatric disorders, as well as in brain tumors. Findings from preclinical models are consistent with the view that the GRPR might play a role in brain disorders, and raise the possibility that GRPR agonists might ameliorate cognitive and social deficits associated with neurological diseases, while antagonists may reduce anxiety and inhibit the growth of some types of brain cancer. Further preclinical and translational studies evaluating the potential therapeutic effects of GRPR ligands are warranted.

  3. Brain purine metabolism and xanthine dehydrogenase/oxidase conversion in hyperammonemia are under control of NMDA receptors and nitric oxide.

    Science.gov (United States)

    Kaminsky, Yury; Kosenko, Elena

    2009-10-19

    In hyperammonemia, a decrease in brain ATP can be a result of adenine nucleotide catabolism. Xanthine dehydrogenase (XD) and xanthine oxidase (XO) are the end steps in the purine catabolic pathway and directly involved in depletion of the adenylate pool in the cell. Besides, XD can easily be converted to XO to produce reactive oxygen species in the cell. In this study, the effects of acute ammonia intoxication in vivo on brain adenine nucleotide pool and xanthine and hypoxanthine, the end degradation products of adenine nucleotides, during the conversion of XD to XO were studied. Injection of rats with ammonium acetate was shown to lead to the dramatic decrease in the ATP level, adenine nucleotide pool size and adenylate energy charge and to the great increase in hypoxanthine and xanthine 11 min after the lethal dose indicating rapid degradation of adenylates. Conversion of XD to XO in hyperammonemic rat brain was evidenced by elevated XO/XD activity ratio. Injection of MK-801, a NMDA receptor blocker, prevented ammonia-induced catabolism of adenine nucleotides and conversion of XD to XO suggesting that in vivo these processes are mediated by activation of NMDA receptors. The in vitro dose-dependent effects of sodium nitroprusside, a NO donor, on XD and XO activities are indicative of the direct modification of the enzymes by nitric oxide. This is the first report evidencing the increase in brain xanthine and hypoxanthine levels and adenine nucleotide breakdown in acute ammonia intoxication and NMDA receptor-mediated prevention of these alterations.

  4. Blood-brain barrier drug delivery of IgG fusion proteins with a transferrin receptor monoclonal antibody.

    Science.gov (United States)

    Pardridge, William M

    2015-02-01

    Biologic drugs are large molecules that do not cross the blood- brain barrier (BBB). Brain penetration is possible following the re-engineering of the biologic drug as an IgG fusion protein. The IgG domain is a MAb against an endogenous BBB receptor such as the transferrin receptor (TfR). The TfRMAb acts as a molecular Trojan horse to ferry the fused biologic drug into the brain via receptor-mediated transport on the endogenous BBB TfR. This review discusses TfR isoforms, models of BBB transport of transferrin and TfRMAbs, and the genetic engineering of TfRMAb fusion proteins, including BBB penetrating IgG-neurotrophins, IgG-decoy receptors, IgG-lysosomal enzyme therapeutics and IgG-avidin fusion proteins, as well as BBB transport of bispecific antibodies formed by fusion of a therapeutic antibody to a TfRMAb targeting antibody. Also discussed are quantitative aspects of the plasma pharmacokinetics and brain uptake of TfRMAb fusion proteins, as compared to the brain uptake of small molecules, and therapeutic applications of TfRMAb fusion proteins in mouse models of neural disease, including Parkinson's disease, stroke, Alzheimer's disease and lysosomal storage disorders. The review covers the engineering of TfRMAb-avidin fusion proteins for BBB targeted delivery of biotinylated peptide radiopharmaceuticals, low-affinity TfRMAb Trojan horses and the safety pharmacology of chronic administration of TfRMAb fusion proteins. The BBB delivery of biologic drugs is possible following re-engineering as a fusion protein with a molecular Trojan horse such as a TfRMAb. The efficacy of this technology will be determined by the outcome of future clinical trials.

  5. Prostaglandin E2 EP2 Receptor Deletion Attenuates Intracerebral Hemorrhage-Induced Brain Injury and Improves Functional Recovery

    Directory of Open Access Journals (Sweden)

    Jenna L. Leclerc

    2015-04-01

    Full Text Available Intracerebral hemorrhage (ICH is a devastating type of stroke characterized by bleeding into the brain parenchyma and secondary brain injury resulting from strong neuroinflammatory responses to blood components. Production of prostaglandin E2 (PGE2 is significantly upregulated following ICH and contributes to this inflammatory response in part through its E prostanoid receptor subtype 2 (EP2. Signaling through the EP2 receptor has been shown to affect outcomes of many acute and chronic neurological disorders; although, not yet explored in the context of ICH. Wildtype (WT and EP2 receptor knockout (EP2−/− mice were subjected to ICH, and various anatomical and functional outcomes were assessed by histology and neurobehavioral testing, respectively. When compared with age-matched WT controls, EP2−/− mice had 41.9 ± 4.7% smaller ICH-induced brain lesions and displayed significantly less ipsilateral hemispheric enlargement and incidence of intraventricular hemorrhage. Anatomical outcomes correlated with improved functional recovery as identified by neurological deficit scoring. Histological staining was performed to begin investigating the mechanisms involved in EP2-mediated neurotoxicity after ICH. EP2−/− mice exhibited 45.5 ± 5.8% and 41.4 ± 8.1% less blood and ferric iron accumulation, respectively. Furthermore, significantly less striatal and cortical microgliosis, striatal and cortical astrogliosis, blood–brain barrier breakdown, and peripheral neutrophil infiltration were seen in EP2−/− mice. This study is the first to suggest a deleterious role for the PGE2-EP2 signaling axis in modulating brain injury, inflammation, and functional recovery following ICH. Targeting the EP2 G protein-coupled receptor may represent a new therapeutic avenue for the treatment of hemorrhagic stroke.

  6. Neurotrophin Signaling via TrkB and TrkC Receptors Promotes the Growth of Brain Tumor-initiating Cells*

    Science.gov (United States)

    Lawn, Samuel; Krishna, Niveditha; Pisklakova, Alexandra; Qu, Xiaotao; Fenstermacher, David A.; Fournier, Michelle; Vrionis, Frank D.; Tran, Nam; Chan, Jennifer A.; Kenchappa, Rajappa S.; Forsyth, Peter A.

    2015-01-01

    Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma. PMID:25538243

  7. Quantitative autoradiographic localization of cholecystokinin receptors in rat and guinea pig brain using 125I-Bolton-Hunter-CCK8

    International Nuclear Information System (INIS)

    Niehoff, D.L.

    1989-01-01

    The autoradiographic localization of receptors for the brain-gut peptide cholecystokinin (CCK) has shown differences in receptor distribution between rat and guinea pig brain. However the full anatomical extent of the differences has not been determined quantitatively. In the present study, 125 I-Bolton-Hunter-CCK8 ( 125 I-BH-CCK8) was employed in a comparative quantitative autoradiographic analysis of the distribution of CCK receptors in these two species. The pharmacological profile of 125 I-BH-CCK8 binding in guinea pig forebrain sections was comparable to those previously reported for rat and human. Statistically significant differences in receptor binding between rat and guinea pig occurred in olfactory bulb, caudate-putamen, amygdala, several cortical areas, ventromedial hypothalamus, cerebellum, and a number of midbrain and brainstem nuclei. The results of this study confirm the presence of extensive species-specific variation in the distribution of CCK receptors, suggesting possible differences in the physiological roles of this peptide in different mammalian species

  8. Expression and role of 5-HT7 receptor in brain and intestine in rats with irritable bowel syndrome.

    Science.gov (United States)

    Zou, Bai-cang; Dong, Lei; Wang, Yan; Wang, Sheng-hao; Cao, Ming-bo

    2007-12-05

    The 5-hydroxytryptamine7 receptor (5-HT(7) receptor, 5-HT(7)R) plays an important role in the regulation of smooth muscle relaxation and visceral sensation and might be involved in the pathogenesis of the gastrointestinal dyskinesia, abdominal pain and visceral paresthesia in irritable bowel syndrome (IBS). The aim of this study was to investigate the role of the 5-HT(7) receptor in the pathogenesis of IBS. A rat model of irritable bowel syndrome with diarrhea (IBS-D) was established by colonic instillation of acetic acid and restraint stress. A rat model with irritable bowel syndrome with constipation (IBS-C) was established by stomach irrigated with 0 - 4 degrees C cool water daily for 14 days. The content and distribution of 5-HT in the brain and gut were examined by immunohistochemistry and the mRNA expression of the 5-HT(7) receptor was determined by fluorescent quantitative reverse transcription polymerase chain reaction. The accumulation of cyclic adenosine monophosphate (cAMP) in all the same tissues was measured by radioimmunity. The models of IBS were reliable by identification. The immunohistochemistry results showed that there were significantly more 5-HT positive cells in the IBS-D group than in the control group in the hippocampus, hypothalamus, jejunum, ileum, proximate colon and distal colon (P intestine is related to the IBS pathogenesis. The up-regulated expression of the 5-HT(7) receptor in the brain and colon might play an important role in the pathogenesis of IBS-C.

  9. [11C]TASP457, a novel PET ligand for histamine H3 receptors in human brain

    International Nuclear Information System (INIS)

    Kimura, Yasuyuki; Seki, Chie; Ikoma, Yoko; Ichise, Masanori; Kawamura, Kazunori; Takahata, Keisuke; Moriguchi, Sho; Nagashima, Tomohisa; Ishii, Tatsuya; Kitamura, Soichiro; Niwa, Fumitoshi; Endo, Hironobu; Yamada, Makiko; Higuchi, Makoto; Zhang, Ming-Rong; Suhara, Tetsuya

    2016-01-01

    The histamine H 3 receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. The receptors are considered a drug target for sleep disorders and neuropsychiatric disorders with cognitive decline. We developed a novel PET ligand for the H 3 receptors, [ 11 C]TASP0410457 ([ 11 C]TASP457), with high affinity, selectivity and favorable kinetic properties in the monkey, and evaluated its kinetics and radiation safety profile for quantifying the H 3 receptors in human brain. Ten healthy men were scanned for 120 min with a PET scanner for brain quantification and three healthy men were scanned for radiation dosimetry after injection of 386 ± 6.2 MBq and 190 ± 7.5 MBq of [ 11 C]TASP457, respectively. For brain quantification, arterial blood sampling and metabolite analysis were performed using high-performance liquid chromatography. Distribution volumes (V T ) in brain regions were determined by compartment and graphical analyses using the Logan plot and Ichise multilinear analysis (MA1). For dosimetry, radiation absorbed doses were estimated using the Medical Internal Radiation Dose scheme. [ 11 C]TASP457 PET showed high uptake (standardized uptake values in the range of about 3 - 6) in the brain and fast washout in cortical regions and slow washout in the pallidum. The two-tissue compartment model and graphical analyses estimated V T with excellent identification using 60-min scan data (about 16 mL/cm 3 in the pallidum, 9 - 14 in the basal ganglia, 6 - 9 in cortical regions, and 5 in the pons), which represents the known distribution of histamine H 3 receptors. For parametric imaging, MA1 is recommended because of minimal underestimation with small intersubject variability. The organs with the highest radiation doses were the pancreas, kidneys, and liver. The effective dose delivered by [ 11 C]TASP457 was 6.9 μSv/MBq. [ 11 C]TASP457 is a useful novel PET ligand for the investigation of the density of histamine H 3

  10. Modulating antibody affinity towards the transferrin receptor to increase brain uptake of anti-transferrin receptor antibody targeted gold nanoparticles

    DEFF Research Database (Denmark)

    Johnsen, Kasper Bendix; Bak, Martin; Melander, Fredrik

    2017-01-01

    by silver enhancement and light microscopy. Electron microscopy showed that the particles had been efficiently endocytosed into the endothelial cells of the BBB. A small fraction of particles could also be detected in the brain parenchyma, which was underscored by measuring the gold content in brain...

  11. Endothelin in human brain and pituitary gland: Presence of immunoreactive endothelin, endothelin messenger ribonucleic acid, and endothelin receptors

    International Nuclear Information System (INIS)

    Takahashi, K.; Ghatei, M.A.; Jones, P.M.; Murphy, J.K.; Lam, H.C.; O'Halloran, D.J.; Bloom, S.R.

    1991-01-01

    The presence of immunoreactive (IR) endothelin, endothelin mRNA, and endothelin receptors in human brain and pituitary gland has been studied by RIA, Northern blot hybridization, and receptor assay. IR endothelin was detected in all five brain regions examined (cerebral cortex, cerebellum, brain stem, basal ganglia, and hypothalamus) (6-10 fmol/g wet wt) and spinal cord (22 +/- 6 fmol/g wet wt, n = 7, mean +/- SEM). Higher concentrations of IR endothelin were found in the pituitary gland (147 +/- 30 fmol/g wet wt). Fast protein liquid chromatographic analysis of the IR endothelin in pituitary gland showed a large IR peak in the position of endothelin-3 and a smaller peak in the position of endothelin-1, whereas IR endothelin in the hypothalamus and brain stem was mainly endothelin-1. Endothelin messenger RNA was detected by Northern blot hybridization in the pituitary but not in hypothalamus. The receptor assay showed that 125I-endothelin-1 binding sites were present in large numbers in all five brain regions but were much less abundant in the pituitary gland. Binding capacity and dissociation constant were 5052 +/- 740 fmol/mg protein and 0.045 +/- 0.007 nM in brain stem and 963 +/- 181 fmol/mg protein and 0.034 +/- 0.009 nM in hypothalamus. In the pituitary gland, there were two classes of binding sites for endothelin with dissociation constants of 0.059 +/- 0.002 nM (binding capacity = 418 +/- 63 fmol/mg protein) and 0.652 +/- 0.103 nM (binding capacity = 1717 +/- 200 fmol/mg protein). Endothelin-1, -2 and -3 were almost equipotent in displacing the binding (IC50 approximately 0.04 nM). These findings are in accord with the possibility that endothelin acts as a neurotransmitter, neuromodulator or neurohormone in man

  12. Glucocorticoid Receptor Related Genes: Genotype And Brain Gene Expression Relationships To Suicide And Major Depressive Disorder

    Science.gov (United States)

    Pantazatos, Spiro P.; Huang, Yung-yu; Rosoklija, Gorazd B.; Dwork, Andrew J.; Burke, Ainsley; Arango, Victoria; Oquendo, Maria A.; Mann, J. John

    2016-01-01

    Introduction We tested the relationship between genotype, gene expression and suicidal behavior and MDD in live subjects and postmortem samples for three genes, associated with the hypothalamic-pituitary-adrenal axis, suicidal behavior and major depressive disorder (MDD); FK506 binding protein 5 (FKBP5), Spindle and kinetochore-associated protein 2 (SKA2) and Glucocorticoid Receptor (NR3C1). Materials and Methods Single-nucleotide polymorphisms (SNPs) and haplotypes were tested for association with suicidal behavior and MDD in a live (N=277) and a postmortem sample (N=209). RNA-seq was used to examine gene and isoform-level brain expression postmortem (Brodmann Area 9) (N=59). Expression quantitative trait loci (eQTL) relationships were examined using a public database (UK Brain Expression Consortium). Results We identified a haplotype within the FKBP5 gene, present in 47% of the live subjects, that was associated with increased risk of suicide attempt (OR=1.58, t=6.03, p=0.014). Six SNPs on this gene, three SNPs on SKA2 and one near NR3C1 showed before-adjustment association with attempted suicide, and two SNPs of SKA2 with suicide death, but none stayed significant after adjustment for multiple testing. Only the SKA2 SNPs were related to expression in the prefrontal cortex. One NR3C1 transcript had lower expression in suicide relative to non-suicide sudden death cases (b=-0.48, SE=0.12, t=-4.02, adjusted p=0.004). Conclusion We have identified an association of FKBP5 haplotype with risk of suicide attempt and found an association between suicide and altered NR3C1 gene expression in the prefrontal cortex. Our findings further implicate hypothalamic pituitary axis dysfunction in suicidal behavior. PMID:27030168

  13. Increased brain damage after ischaemic stroke in mice lacking the chemokine receptor CCR5

    Science.gov (United States)

    Sorce, S; Bonnefont, J; Julien, S; Marq-Lin, N; Rodriguez, I; Dubois-Dauphin, M; Krause, KH

    2010-01-01

    Background and purpose: The chemokine receptor CCR5 is well known for its function in immune cells; however, it is also expressed in the brain, where its specific role remains to be elucidated. Because genetic factors may influence the risk of developing cerebral ischaemia or affect its clinical outcome, we have analysed the role of CCR5 in experimental stroke. Experimental approach: Permanent cerebral ischaemia was performed by occlusion of the middle cerebral artery in wild-type and CCR5-deficient mice. Locomotor behaviour, infarct size and histochemical alterations were analysed at different time points after occlusion. Key results: The cerebral vasculature was comparable in wild-type and CCR5-deficient mice. However, the size of the infarct and the motor deficits after occlusion were markedly increased in CCR5-deficient mice as compared with wild type. No differences between wild-type and CCR5-deficient mice were elicited by occlusion with respect to the morphology and abundance of astrocytes and microglia. Seven days after occlusion the majority of CCR5-deficient mice displayed neutrophil invasion in the infarct region, which was not observed in wild type. As compared with wild type, the infarct regions of CCR5-deficient mice were characterized by increased neuronal death. Conclusions and implications: Lack of CCR5 increased the severity of brain injury following occlusion of the middle cerebral artery. This is of particular interest with respect to the relatively frequent occurrence of CCR5 deficiency in the human population (1–2% of the Caucasian population) and the advent of CCR5 inhibitors as novel drugs. PMID:20423342

  14. Estradiol receptors mediate estradiol-induced inhibition of mitochondrial Ca^{2+} efflux in rat caudate nucleus and brain stem

    OpenAIRE

    PETROVIC, SNJEZANA; MILOSEVIC, MAJA; RISTIC-MEDIC, DANIJELA; VELICKOVIC, NATASA; DRAKULIC, DUNJA; GRKOVIC, IVANA; HORVAT, ANICA

    2015-01-01

    Our earlier studies found that in vitro estradiol modulates mitochondrial Ca2+ transport in discrete brain regions. The present study examined the role of estradiol receptors (ERs) in estradiol-induced inhibition of Ca^{2+} efflux from synaptosomal mitochondria isolated from rat caudate nuclei and brain stems. Radioactively labeled CaCl_2 (0.6?0.75 µCi ^45CaCl_{2}) was used for Ca^{2+} transport monitoring. The results revealed that in the presence of ER antagonist 7\\alpha,17ß-[9[(4,4,5,5,5-...

  15. Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain

    DEFF Research Database (Denmark)

    Borg, J; Cervenka, S; Kuja-Halkola, R

    2016-01-01

    The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about...... and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A...

  16. The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum.

    Science.gov (United States)

    Centonze, Diego; Rossi, Silvia; Napoli, Ilaria; Mercaldo, Valentina; Lacoux, Caroline; Ferrari, Francesca; Ciotti, Maria Teresa; De Chiara, Valentina; Prosperetti, Chiara; Maccarrone, Mauro; Fezza, Filomena; Calabresi, Paolo; Bernardi, Giorgio; Bagni, Claudia

    2007-08-15

    Dopamine D(2) receptor (D(2)DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor-associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D(2) receptors in this brain area are essentially obscure. We have studied the physiological responses of the D(2)DR stimulations in mice lacking the brain cytoplasmic RNA BC1, a small noncoding dendritically localized RNA that is supposed to play a role in mRNA translation. We show that the efficiency of D(2)-mediated transmission regulating striatal GABA synapses is under the control of BC1 RNA, through a negative influence on D(2) receptor protein level affecting the functional pool of receptors. Ablation of the BC1 gene did not result in widespread dysregulation of synaptic transmission, because the sensitivity of cannabinoid CB(1) receptors was intact in the striatum of BC1 knock-out (KO) mice despite D(2) and CB(1) receptors mediated similar electrophysiological actions. Interestingly, the fragile X mental retardation protein FMRP, one of the multiple BC1 partners, is not involved in the BC1 effects on the D(2)-mediated transmission. Because D(2)DR mRNA is apparently equally translated in the BC1-KO and wild-type mice, whereas the protein level is higher in BC1-KO mice, we suggest that BC1 RNA controls D(2)DR indirectly, probably regulating translation of molecules involved in D(2)DR turnover and/or stability.

  17. Sigma-1 receptor chaperone and brain-derived neurotrophic factor: emerging links between cardiovascular disease and depression.

    Science.gov (United States)

    Hashimoto, Kenji

    2013-01-01

    Epidemiological studies have demonstrated a close relationship between depression and cardiovascular disease (CVD). Although it is known that the central nervous system (CNS) contributes to this relationship, the detailed mechanisms involved in this process remain unclear. Recent studies suggest that the endoplasmic reticulum (ER) molecular chaperone sigma-1 receptor and brain-derived neurotrophic factor (BDNF) play a role in the pathophysiology of CVD and depression. Several meta-analysis studies have showed that levels of BDNF in the blood of patients with major depressive disorder (MDD) are lower than normal controls, indicating that blood BDNF might be a biomarker for depression. Furthermore, blood levels of BDNF in patients with CVD are also lower than normal controls. A recent study using conditional BDNF knock-out mice in animal models of myocardial infarction highlighted the role of CNS-mediated mechanisms in the cardioprotective effects of BDNF. In addition, a recent study shows that decreased levels of sigma-1 receptor in the mouse brain contribute to the association between heart failure and depression. Moreover, sigma-1 receptor agonists, including the endogenous neurosteroid dehydroepiandosterone (DHEA) and the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, show potent cardioprotective and antidepressive effects in rodents, via sigma-1 receptor stimulation. Interestingly, agonist activation of sigma-1 receptors increased the secretion of mature BDNF from its precursor proBDNF via chaperone activity in the ER. Given the role of ER stress in the pathophysiology of CVD and MDD, the author will discuss the potential link between sigma-1 receptors and BDNF-TrkB pathway in the pathophysiology of these two diseases. Finally, the author will make a case for potent sigma-1 receptor agonists and TrkB agonists as new potential therapeutic drugs for depressive patients with CVD. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Neurokinin-3 Receptor Binding in Guinea Pig, Monkey, and Human Brain: In Vitro and in Vivo Imaging Using the Novel Radioligand, [18F]Lu AF10628.

    Science.gov (United States)

    Varnäs, Katarina; Finnema, Sjoerd J; Stepanov, Vladimir; Takano, Akihiro; Tóth, Miklós; Svedberg, Marie; Møller Nielsen, Søren; Khanzhin, Nikolay A; Juhl, Karsten; Bang-Andersen, Benny; Halldin, Christer; Farde, Lars

    2016-08-01

    Previous autoradiography studies have suggested a marked interspecies variation in the neuroanatomical localization and expression levels of the neurokinin 3 receptor, with high density in the brain of rat, gerbil, and guinea pig, but at the time offered no conclusive evidence for its presence in the human brain. Hitherto available radioligands have displayed low affinity for the human neurokinin 3 receptor relative to the rodent homologue and may thus not be optimal for cross-species analyses of the expression of this protein. A novel neurokinin 3 receptor radioligand, [(18)F]Lu AF10628 ((S)-N-(cyclobutyl(3-fluorophenyl)methyl)-8-fluoro-2-((3-[(18)F]-fluoropropyl)amino)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide), was synthesized and used for autoradiography studies in cryosections from guinea pig, monkey, and human brain as well as for positron emission tomography studies in guinea pig and monkey. The results confirmed previous observations of interspecies variation in the neurokinin 3 receptor brain localization with more extensive distribution in guinea pig than in primate brain. In the human brain, specific binding to the neurokinin 3 receptor was highest in the amygdala and in the hypothalamus and very low in other regions examined. Positron emission tomography imaging showed a pattern consistent with that observed using autoradiography. The radioactivity was, however, found to accumulate in skull bone, which limits the use of this radioligand for in vivo quantification of neurokinin 3 receptor binding. Species differences in the brain distribution of neurokinin 3 receptors should be considered when using animal models for predicting human neurokinin 3 receptor pharmacology. For positron emission tomography imaging of brain neurokinin 3 receptors, additional work is required to develop a radioligand with more favorable in vivo properties. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  19. Transcytosis in the blood–cerebrospinal fluid barrier of the mouse brain with an engineered receptor/ligand system

    Directory of Open Access Journals (Sweden)

    Héctor R Méndez-Gómez

    Full Text Available Crossing the blood–brain and the blood–cerebrospinal fluid barriers (BCSFB is one of the fundamental challenges in the development of new therapeutic molecules for brain disorders because these barriers prevent entry of most drugs from the blood into the brain. However, some large molecules, like the protein transferrin, cross these barriers using a specific receptor that transports them into the brain. Based on this mechanism, we engineered a receptor/ligand system to overcome the brain barriers by combining the human transferrin receptor with the cohesin domain from Clostridium thermocellum, and we tested the hybrid receptor in the choroid plexus of the mouse brain with a dockerin ligand. By expressing our receptor in choroidal ependymocytes, which are part of the BCSFB, we found that our systemically administrated ligand was able to bind to the receptor and accumulate in ependymocytes, where some of the ligand was transported from the blood side to the brain side.

  20. Binding characteristics of brain-derived neurotrophic factor to its receptors on neurons from the chick embryo

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez-Tebar, A.; Barde, Y.A.

    1988-09-01

    Brain-derived neurotrophic factor (BDNF), a protein known to support the survival of embryonic sensory neurons and retinal ganglion cells, was derivatized with 125I-Bolton-Hunter reagent and obtained in a biologically active, radioactive form (125I-BDNF). Using dorsal root ganglion neurons from chick embryos at 9 d of development, the basic physicochemical parameters of the binding of 125I-BDNF with its receptors were established. Two different classes of receptors were found, with dissociation constants of 1.7 x 10(-11) M (high-affinity receptors) and 1.3 x 10(-9) M (low-affinity receptors). Unlabeled BDNF competed with 125I-BDNF for binding to the high-affinity receptors with an inhibition constant essentially identical to the dissociation constant of the labeled protein: 1.2 x 10(-11) M. The association and dissociation rates from both types of receptors were also determined, and the dissociation constants calculated from these kinetic experiments were found to correspond to the results obtained from steady-state binding. The number of high-affinity receptors (a few hundred per cell soma) was 15 times lower than that of low-affinity receptors. No high-affinity receptors were found on sympathetic neurons, known not to respond to BDNF, although specific binding of 125I-BDNF to these cells was detected at a high concentration of the radioligand. These results are discussed and compared with those obtained with nerve growth factor on the same neuronal populations.

  1. Binding characteristics of brain-derived neurotrophic factor to its receptors on neurons from the chick embryo

    International Nuclear Information System (INIS)

    Rodriguez-Tebar, A.; Barde, Y.A.

    1988-01-01

    Brain-derived neurotrophic factor (BDNF), a protein known to support the survival of embryonic sensory neurons and retinal ganglion cells, was derivatized with 125I-Bolton-Hunter reagent and obtained in a biologically active, radioactive form (125I-BDNF). Using dorsal root ganglion neurons from chick embryos at 9 d of development, the basic physicochemical parameters of the binding of 125I-BDNF with its receptors were established. Two different classes of receptors were found, with dissociation constants of 1.7 x 10(-11) M (high-affinity receptors) and 1.3 x 10(-9) M (low-affinity receptors). Unlabeled BDNF competed with 125I-BDNF for binding to the high-affinity receptors with an inhibition constant essentially identical to the dissociation constant of the labeled protein: 1.2 x 10(-11) M. The association and dissociation rates from both types of receptors were also determined, and the dissociation constants calculated from these kinetic experiments were found to correspond to the results obtained from steady-state binding. The number of high-affinity receptors (a few hundred per cell soma) was 15 times lower than that of low-affinity receptors. No high-affinity receptors were found on sympathetic neurons, known not to respond to BDNF, although specific binding of 125I-BDNF to these cells was detected at a high concentration of the radioligand. These results are discussed and compared with those obtained with nerve growth factor on the same neuronal populations

  2. Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.

    Directory of Open Access Journals (Sweden)

    Takeaki Saijo

    Full Text Available A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT(1A receptor, called Wf-516 (structural formula: (2S-1-[4-(3,4-dichlorophenylpiperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-ylbenzo[b]furan-4-yloxy]propan-2-ol monohydrochloride, has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT(1A receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT(1A receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT(1A receptors. In addition, [(35S]guanosine 5'-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT(1A receptors. This finding has lent support to reports that diverse partial agonists for 5-HT(1A receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

  3. Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.

    Science.gov (United States)

    Saijo, Takeaki; Maeda, Jun; Okauchi, Takashi; Maeda, Jun-ichi; Morio, Yasunori; Kuwahara, Yasuhiro; Suzuki, Masayuki; Goto, Nobuharu; Fukumura, Toshimitsu; Suhara, Tetsuya; Higuchi, Makoto

    2012-01-01

    A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT(1A)) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT(1A) receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT(1A) receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT(1A) receptors. In addition, [(35)S]guanosine 5'-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT(1A) receptors. This finding has lent support to reports that diverse partial agonists for 5-HT(1A) receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

  4. Soluble (Prorenin Receptor and Obstructive Sleep Apnea Syndrome: Oxidative Stress in Brain?

    Directory of Open Access Journals (Sweden)

    Kazuhiro Takahashi

    2017-06-01

    Full Text Available (Prorenin receptor ((PRR is a multi-functional molecule that is related to both the renin-angiotensin system (RAS and vacuolar H+-ATPase (v-ATPase, an ATP-dependent multi-subunit proton pump. Soluble (PRR (s(PRR, which consists of the extracellular domain of (PRR, is present in blood and urine. Elevated plasma s(PRR concentrations are reported in patients with chronic kidney disease and pregnant women with hypertension or diabetes mellitus. In addition, we have shown that plasma s(PRR concentrations are elevated in patients with obstructive sleep apnea syndrome (OSAS. Interestingly, the levels are elevated in parallel with the severity of OSAS, but are not related to the presence of hypertension or the status of the circulating RAS in OSAS. It is known that v-ATPase activity protects cells from endogenous oxidative stress, and loss of v-ATPase activity results in chronic oxidative stress. We hypothesize that hypoxia and subsequent oxidative stress, perhaps in the brain, may be one of the factors that elevate plasma s(PRR levels in OSAS.

  5. Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist.

    Science.gov (United States)

    Steiner, Michel A; Gatfield, John; Brisbare-Roch, Catherine; Dietrich, Hendrik; Treiber, Alexander; Jenck, Francois; Boss, Christoph

    2013-06-01

    Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Dopamine D2 receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse

    OpenAIRE

    Oien, Derek B.; Ortiz, Andrea N.; Rittel, Alexander G.; Dobrowsky, Rick T.; Johnson, Michael A.; Levant, Beth; Fowler, Stephen C.; Moskovitz, Jackob

    2010-01-01

    Previous research suggests that brain oxidative stress and altered rodent locomotor behavior are linked. We observed bio-behavioral changes in methionine sulfoxide reductase A knockout mice associated with abnormal dopamine signaling. Compromised ability of these knockout mice to reduce methionine sulfoxide enhances accumulation of sulfoxides in proteins. We examined the dopamine D2-receptor function and expression, which has an atypical arrangement and quantity of methionine residues. Indeed...

  7. Constitutive androstane receptor upregulates Abcb1 and Abcg2 at the blood-brain barrier after CITCO activation.

    Science.gov (United States)

    Lemmen, Julia; Tozakidis, Iasson E P; Bele, Prachee; Galla, Hans-Joachim

    2013-03-21

    ATP-driven efflux transporters are considered to be the major hurdle in the treatment of central nervous system (CNS) diseases. Abcb1 (P-glycoprotein) and Abcg2 (breast cancer resistance protein/brain multidrug resistance protein) belong to the best known ABC-transporters. These ABC-transporters limit the permeability of the blood-brain barrier and protect the brain against toxic compounds in the blood but on the other hand they also reduce the efficacy of CNS pharmacotherapy. Even after 40 years of extensive research, the regulatory mechanisms of these efflux transporters are still not completely understood. To unravel the efflux transporter regulation, we analyzed the effect of the nuclear receptor CAR (constitutive androstane receptor) on the expression of Abcb1 and Abcg2 in primary cultures of porcine brain capillary endothelial cells (PBCEC). CAR is a xenobiotic-activated transcription factor, which is, like the other important nuclear receptor pregnane X receptor (PXR), highly expressed in barrier tissue and known to be a positive regulator of ABC-transporters. We demonstrate that activation of porcine CAR by the human CAR (hCAR) ligand CITCO (6-(4-chlorophenyl)-imidazo[2,1-b]thiazole-5-carbaldehyde) leads to an up-regulation of both transporters, whereas the mouse-specific CAR ligand TCPOBOP (1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene) had no effect on transporter expression. The stimulation of PBCEC with CITCO caused a significant up-regulation of both efflux-transporters on RNA-level, protein level and transport level. Furthermore the additional application of a CAR inhibitor significantly decreased the transporter expression to control niveau. In conclusion our data prove CAR activation only by the human ligand CITCO leading to an increased ABC-transporter expression and transport activity. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Distribution of 5HT2A receptors in the human brain: Comparison of data in vivo and post mortem

    International Nuclear Information System (INIS)

    Forutan, F.; Estalji, S.; Beu, M.; Nikolaus, S.; Vosberg, H.; Mueller-Gaertner, H.W.; Larisch, R.; Hamacher, K.; Coenen, H.H.

    2002-01-01

    Aim: The study presented here firstly compars the distribution of the binding potential of the serotonin-5HT 2A receptor as measured in vivo with data of receptor density taken from literature. Secondly, the sensitivity of the method to detect gradual differences in receptor densities is evaluated. Methods: Positron emission tomography (PET) studies were carried out in 6 healthy volunteers using the selective serotonin-5HT 2A ligand 18 F-altanserin. The binding potential was quantified in 12 regions using Logan's graphical method and the equilibrium method. These data were compared to the distribution of receptor density as taken from literature. Results: The binding data in vivo correlated to autoradiography data (post mortem) with r = 0.83 (Pearson regression coefficient; p 18 F-altanserin and PET in healthy volunteers and the true autoradiographically determined distribution of 5HT 2A receptors in human brains. The in vivo method seems to be sensitive enough to detect changes in receptor density of more than 18%. (orig.)

  9. (11)C-MK-8278 PET as a tool for pharmacodynamic brain occupancy of histamine 3 receptor inverse agonists.

    Science.gov (United States)

    Van Laere, Koenraad J; Sanabria-Bohórquez, Sandra M; Mozley, David P; Burns, Donald H; Hamill, Terence G; Van Hecken, Anne; De Lepeleire, Inge; Koole, Michel; Bormans, Guy; de Hoon, Jan; Depré, Marleen; Cerchio, Kristine; Plalcza, John; Han, Lingling; Renger, John; Hargreaves, Richard J; Iannone, Robert

    2014-01-01

    The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity. Using PET and a novel high-affinity and selective radioligand (11)C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level. The mean effective dose for (11)C-MK-8278 was 5.4 ± 1.1 μSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses. (11)C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules.

  10. Distribution of the a2, a3, and a5 nicotinic acetylcholine receptor subunits in the chick brain

    Directory of Open Access Journals (Sweden)

    Torrão A.S.

    1997-01-01

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are ionotropic receptors comprised of a and ß subunits. These receptors are widely distributed in the central nervous system, and previous studies have revealed specific patterns of localization for some nAChR subunits in the vertebrate brain. In the present study we used immunohistochemical methods and monoclonal antibodies to localize the a2, a3, and a5 nAChR subunits in the chick mesencephalon and diencephalon. We observed a differential distribution of these three subunits in the chick brain, and showed that the somata and neuropil of many central structures contain the a5 nAChR subunit. The a2 and a3 subunits, on the other hand, exhibited a more restricted distribution than a5 and other subunits previously studied, namely a7, a8 and ß2. The patterns of distribution of the different nAChR subunits suggest that neurons in many brain structures may contain several subtypes of nAChRs and that in a few regions one particular subtype may determine the cholinergic nicotinic responses

  11. Serotoninergic receptors in brain tissue: properties and identification of various 3H-ligand binding sites in vitro

    International Nuclear Information System (INIS)

    Leysen, J.E.

    1981-01-01

    In vitro binding studies to serotoninergic receptors were performed using 3 H-LSD, 3 H-5-HT and 3 H-spiperone. An overwiew is given on findings using these three ligands with respect to the following: localization of specific binding sites, in various animal species, the regional distribution in the brain and periphery, the subcellular and cellular distribution. Properties of the binding sites, influence of the composition of the assay medium, binding kinetic properties, receptor regulation in vivo. Identity of the binding sites, differences between site for various 3 H-ligands, pharmacological specificity of the membranous binding sites, chemical composition of the macromolecular complex constituting the binding site. Function of the receptor. Binding affinities of 44 compounds were measured in binding assays using 3 H-spiperone and 3 H-LSD with rat frontal cortex membrane preparations and using 3 H-5-HT and 3 H-LSD with rat hippocampal membrane preparations

  12. Expression and distribution of the glucocorticoid receptor DlGR1 in the teleost Dicentrarchus labrax brain

    Directory of Open Access Journals (Sweden)

    Nicolò Parrinello

    2010-01-01

    Full Text Available Cortisol is the main corticosteroid secreted by the interrenal cells of the head kidney and it exerts a role in mantaining the omeostatic status in fish. In teleosts its effects are mediated through intracellular receptors expressed in several tissues, that are ligand-dependent transcription factors by binding to specific tissue DNA sequences. In Dicentrarchus labrax we previously cloned and sequenced a glucocorticoid receptor, DlGR1, isolated from leukocytes of peritoneal cavity. In this work we showed mRNA expression and tissue immunohistochemical localization of brain DlGR1 by in situ hybridization assays, with a riboprobe with DlGR1 cDNA trascriptional activation domain, and by immunohistochemical methods, using a specific antibody for a selected sequence of the receptor tran- scriptional domain. The mRNA and the protein are expressed in pyramidal cells of the optic lobe and in the small globular neurons of the diencephalon.

  13. EANM procedure guidelines for brain neurotransmission SPECT/PET using dopamine D2 receptor ligands, version 2

    DEFF Research Database (Denmark)

    Van Laere, Koen; Varrone, Andrea; Booij, Jan

    2010-01-01

    receptor SPECT or PET studies, and to achieve a high quality standard of dopamine D2 receptor imaging, which will increase the impact of this technique in neurological practice.The present document is an update of the first guidelines for SPECT using D2 receptor ligands labelled with (123)I [1......The guidelines summarize the current views of the European Association of Nuclear Medicine Neuroimaging Committee (ENC). The aims of the guidelines are to assist nuclear medicine practitioners in making recommendations, performing, interpreting and reporting the results of clinical dopamine D2......] and was guided by the views of the Society of Nuclear Medicine Brain Imaging Council [2], and the individual experience of experts in European countries. The guidelines intend to present information specifically adapted to European practice. The information provided should be taken in the context of local...

  14. Synthesis and evaluation of [/sup 125/I]iodothienoperidol as a potential receptor site directed brain imaging agent

    International Nuclear Information System (INIS)

    Hanson, R.N.; Franke, L.A.; Astik, R.R.

    1985-01-01

    This study was undertaken to design and evaluate radioligands for the noninvasive quantification of dopamine receptors in the brain. The approach involved the preparation of the iodothienyl analog I of haloperidol II, a well characterized dopamine antagonist which has been labeled with F-18 and C-11. The synthesis involved the addition of 5-trimethylstannyl-2-thienyllithium so the piperidone intermediate. The product was characterized by spectroscopic and analytic methods and radioiodinated via electrophilic iododestannylation to yield the product in 75-85% isolated yield. The tissue distribution of the radiochemical was evaluated in rats as a function of time, 0.25-2 hrs, and in the presence or absence of haloperidol (1 mg/kg) to measure receptor binding. The results indicated that the 0.25 h uptake in the brain was high (2.2% ID) and that the washout of the activity was relatively slow, 1.3% ID present at 2 hr. The Br/B1 values remained relatively constant over that time interval (9.3-12.1:1). Coadministration of 1 mg/kg haloperidol markedly reduced the uptake in the brain at 0.25 and 2 hr (55% and 62%) with much less of an effect on the nontarget tissues. The study indicates that the authors have prepared a radiotracer, labeled with iodine, that demonstrates both good brain uptake and selectivity as well as a specific binding site component

  15. Binge eating disorder and morbid obesity are associated with lowered mu-opioid receptor availability in the brain.

    Science.gov (United States)

    Joutsa, Juho; Karlsson, Henry K; Majuri, Joonas; Nuutila, Pirjo; Helin, Semi; Kaasinen, Valtteri; Nummenmaa, Lauri

    2018-03-09

    Both morbid obesity and binge eating disorder (BED) have previously been linked with aberrant brain opioid function. Behaviorally these two conditions are however different suggesting also differences in neurotransmitter function. Here we directly compared mu-opioid receptor (MOR) availability between morbidly obese and BED subjects. Seven BED and nineteen morbidly obese (non-BED) patients, and thirty matched control subjects underwent positron emission tomography (PET) with MOR-specific ligand [ 11 C]carfentanil. Both subjects with morbid obesity and BED had widespread reduction in [ 11 C]carfentanil binding compared to control subjects. However, there was no significant difference in brain MOR binding between subjects with morbid obesity and BED. Thus, our results indicate that there is common brain opioid abnormality in behaviorally different eating disorders involving obesity. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression

    Directory of Open Access Journals (Sweden)

    Madrigal José LM

    2011-11-01

    Full Text Available Abstract Background There is a pressing need to identify novel pathophysiological pathways relevant to depression that can help to reveal targets for the development of new medications. Toll-like receptor 4 (TLR-4 has a regulatory role in the brain's response to stress. Psychological stress may compromise the intestinal barrier, and increased gastrointestinal permeability with translocation of lipopolysaccharide (LPS from Gram-negative bacteria may play a role in the pathophysiology of major depression. Methods Adult male Sprague-Dawley rats were subjected to chronic mild stress (CMS or CMS+intestinal antibiotic decontamination (CMS+ATB protocols. Levels of components of the TLR-4 signaling pathway, of LPS and of different inflammatory, oxidative/nitrosative and anti-inflammatory mediators were measured by RT-PCR, western blot and/or ELISA in brain prefrontal cortex. Behavioral despair was studied using Porsolt's test. Results CMS increased levels of TLR-4 and its co-receptor MD-2 in brain as well as LPS and LPS-binding protein in plasma. In addition, CMS also increased interleukin (IL-1β, COX-2, PGE2 and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-PGJ2 in brain tissue. Intestinal decontamination reduced brain levels of the pro-inflammatory parameters and increased 15d-PGJ2, however this did not affect depressive-like behavior induced by CMS. Conclusions Our results suggest that LPS from bacterial translocation is responsible, at least in part, for the TLR-4 activation found in brain after CMS, which leads to release of inflammatory mediators in the CNS. The use of Gram-negative antibiotics offers a potential therapeutic approach for the adjuvant treatment of depression.

  17. Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature.

    Science.gov (United States)

    Carnevale, Daniela; Mascio, Giada; D'Andrea, Ivana; Fardella, Valentina; Bell, Robert D; Branchi, Igor; Pallante, Fabio; Zlokovic, Berislav; Yan, Shirley Shidu; Lembo, Giuseppe

    2012-07-01

    Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by transverse aortic constriction, leading to alterations typical of Alzheimer disease, such as amyloid plaques, neuroinflammation, blood-brain barrier dysfunction, and cognitive impairment, shown here for the first time. The aim of this work was to investigate the mechanisms involved in Alzheimer disease of hypertensive mice. We focused on receptor for advanced glycation end products (RAGE) that critically regulates Aβ transport at the blood-brain barrier and could be influenced by vascular factors. The hypertensive challenge had an early and sustained effect on RAGE upregulation in brain vessels of the cortex and hippocampus. Interestingly, RAGE inhibition protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal Aβ deposition. The increased RAGE expression in transverse aortic coarctation mice was induced by increased circulating advanced glycation end products and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an advanced glycation end product inhibitor or antioxidant prevented the development of Alzheimer traits. So far, Alzheimer pathology in experimental animal models has been recognized using only transgenic mice overexpressing amyloid precursor. This is the first study demonstrating that a chronic vascular insult can activate brain vascular RAGE, favoring parenchymal Aβ deposition and the onset of cognitive deterioration. Overall we demonstrate that RAGE activation in brain vessels is a crucial pathogenetic event in hypertension-induced Alzheimer disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer disease.

  18. Expression of Shiga toxin 2e glycosphingolipid receptors of primary porcine brain endothelial cells and toxin-mediated breakdown of the blood-brain barrier.

    Science.gov (United States)

    Meisen, Iris; Rosenbrück, Regina; Galla, Hans-Joachim; Hüwel, Sabine; Kouzel, Ivan U; Mormann, Michael; Karch, Helge; Müthing, Johannes

    2013-06-01

    Shiga toxin (Stx) 2e, released by certain Stx-producing Escherichia coli, is presently the best characterized virulence factor responsible for pig edema disease, which is characterized by hemorrhagic lesions, neurological disorders and often fatal outcomes. Although Stx2e-mediated brain vascular injury is the key event in development of neurologic signs, the glycosphingolipid (GSL) receptors of Stx2e and toxin-mediated impairment of pig brain endothelial cells have not been investigated so far. Here, we report on the detailed structural characterization of Stx2e receptors globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer), which make up the major neutral GSLs in primary porcine brain capillary endothelial cells (PBCECs). Various Gb3Cer and Gb4Cer lipoforms harboring sphingenine (d18:1) or sphinganine (d18:0) and mostly a long-chain fatty acid (C20-C24) were detected. A notable batch-to-batch heterogeneity of primary endothelial cells was observed regarding the extent of ceramide hydroxylation of Gb3Cer or Gb4Cer species. Gb3Cer, Gb4Cer and sphingomyelin preferentially distribute to detergent-resistant membrane fractions and can be considered lipid raft markers in PBCECs. Moreover, we employed an in vitro model of the blood-brain barrier (BBB), which exhibited strong cytotoxic effects of Stx2e on the endothelial monolayer and a rapid collapse of the BBB. These data strongly suggest the involvement of Stx2e in cerebral vascular damage with resultant neurological disturbance characteristic of edema disease.

  19. Quantification of 5-HT{sub 1A} receptors in human brain using p-MPPF kinetic modelling and PET

    Energy Technology Data Exchange (ETDEWEB)

    Sanabria-Bohorquez, S.M.; Veraart, C. [Neural Rehabilitation Engineering Lab., Univ. Catholique de Louvain, Brussels (Belgium); Biver, F.; Damhaut, P.; Wikler, D.; Goldman, S. [PET/Biomedical Cyclotron Unit, Univ. Libre de Bruxelles (Belgium)

    2002-01-01

    Serotonin-1A (5-HT{sub 1A}) receptors are implicated in neurochemical mechanisms underlying anxiety and depression and their treatment. Animal studies have suggested that 4-(2'-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-[{sup 18}F]fluorobenzamido] ethyl] piperazine (p-MPPF) may be a suitable positron emission tomography (PET) tracer of 5-HT{sub 1A} receptors. To test p-MPPF in humans, we performed 60-min dynamic PET scans in 13 healthy volunteers after single bolus injection. Metabolite quantification revealed a fast decrease in tracer plasma concentration, such that at 5 min post injection about 25% of the total radioactivity in plasma corresponded to p-MPPF. Radioactivity concentration was highest in hippocampus, intermediate in neocortex and lowest in basal ganglia and cerebellum. The interactions between p-MPPF and 5-HT{sub 1A} receptors were described using linear compartmental models with plasma input and reference tissue approaches. The two quantification methods provided similar results which are in agreement with previous reports on 5-HT{sub 1A} receptor brain distribution. In conclusion, our results show that p-MPPF is a suitable PET radioligand for 5-HT{sub 1A} receptor human studies. (orig.)

  20. Pituitary and brain D2 receptor density measured in vitro and in vivo in EEDQ treated male rats

    International Nuclear Information System (INIS)

    Ekman, A.; Eriksson, E.

    1991-01-01

    The effect of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on dopamine D2 receptor density in rat pituitary and brain was measured using in vitro and in vivo radioligand binding techniques. In the in vitro radioligand binding experiments EEDQ was found to reduce the density (B max ) of [ 3 H]-spiperone binding sites in the striatum by 86% while in the pituitary the corresponding decrease was only 37%. The affinity (K D ) of the remaining striatal and pituitary D2 receptors was not different in EEDQ treated animals as compared to controls. When D2 receptor density was measured in vivo the effect of EEDQ was less pronounced. Thus, in rats given EEDQ the specific binding of either of the two D2 ligands [ 3 H]-raclopride or [ 3 H]-spiperone in striatum and in the limbic forebrain was reduced by 45-62%; moreover, no significant decrease in pituitary D2 receptor density was observed. The data are discussed in relation to the finding that the same dose of EEDQ that failed to influence pituitary D2 receptor density as measured in vivo effectively antagonizes the prolactin decreasing effect of the partial D2 agonist (-)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine [(-)-3-PPP

  1. Kinetic analysis of transport and opioid receptor binding of ( sup 3 H)(-)-cyclofoxy in rat brain in vivo: Implications for human studies

    Energy Technology Data Exchange (ETDEWEB)

    Sawada, Y.; Kawai, R.; McManaway, M.; Otsuki, H.; Rice, K.C.; Patlak, C.S.; Blasberg, R.G. (National Institutes of Health, Bethesda, MD (USA))

    1991-03-01

    (3H)Cyclofoxy (CF: 17-cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta-fluoromorp hinan) is an opioid antagonist with affinity to both mu and kappa subtypes that was synthesized for quantitative evaluation of opioid receptor binding in vivo. Two sets of experiments in rats were analyzed. The first involved determining the metabolite-corrected blood concentration and tissue distribution of CF in brain 1 to 60 min after i.v. bolus injection. The second involved measuring brain washout for 15 to 120 s following intracarotid artery injection of CF. A physiologically based model and a classical compartmental pharmacokinetic model were compared. The models included different assumptions for transport across the blood-brain barrier (BBB); estimates of nonspecific tissue binding and specific binding to a single opiate receptor site were found to be essentially the same with both models. The nonspecific binding equilibrium constant varied modestly in different brain structures (Keq = 3-9), whereas the binding potential (BP) varied over a much broader range (BP = 0.6-32). In vivo estimates of the opioid receptor dissociation constant were similar for different brain structures (KD = 2.1-5.2 nM), whereas the apparent receptor density (Bmax) varied between 1 (cerebellum) and 78 (thalamus) pmol/g of brain. The receptor dissociation rate constants in cerebrum (k4 = 0.08-0.16 min-1; koff = 0.16-0.23 min-1) and brain vascular permeability (PS = 1.3-3.4 ml/min/g) are sufficiently high to achieve equilibrium conditions within a reasonable period of time. Graphical analysis of the data is inappropriate due to the high tissue-loss rate constant for CF in brain. From these findings, CF should be a very useful opioid receptor ligand for the estimation of the receptor binding parameters in human subjects using (18F)CF and positron emission tomography.

  2. Kinetic analysis of transport and opioid receptor binding of [3H](-)-cyclofoxy in rat brain in vivo: Implications for human studies

    International Nuclear Information System (INIS)

    Sawada, Y.; Kawai, R.; McManaway, M.; Otsuki, H.; Rice, K.C.; Patlak, C.S.; Blasberg, R.G.

    1991-01-01

    [3H]Cyclofoxy (CF: 17-cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta-fluoromorp hinan) is an opioid antagonist with affinity to both mu and kappa subtypes that was synthesized for quantitative evaluation of opioid receptor binding in vivo. Two sets of experiments in rats were analyzed. The first involved determining the metabolite-corrected blood concentration and tissue distribution of CF in brain 1 to 60 min after i.v. bolus injection. The second involved measuring brain washout for 15 to 120 s following intracarotid artery injection of CF. A physiologically based model and a classical compartmental pharmacokinetic model were compared. The models included different assumptions for transport across the blood-brain barrier (BBB); estimates of nonspecific tissue binding and specific binding to a single opiate receptor site were found to be essentially the same with both models. The nonspecific binding equilibrium constant varied modestly in different brain structures (Keq = 3-9), whereas the binding potential (BP) varied over a much broader range (BP = 0.6-32). In vivo estimates of the opioid receptor dissociation constant were similar for different brain structures (KD = 2.1-5.2 nM), whereas the apparent receptor density (Bmax) varied between 1 (cerebellum) and 78 (thalamus) pmol/g of brain. The receptor dissociation rate constants in cerebrum (k4 = 0.08-0.16 min-1; koff = 0.16-0.23 min-1) and brain vascular permeability (PS = 1.3-3.4 ml/min/g) are sufficiently high to achieve equilibrium conditions within a reasonable period of time. Graphical analysis of the data is inappropriate due to the high tissue-loss rate constant for CF in brain. From these findings, CF should be a very useful opioid receptor ligand for the estimation of the receptor binding parameters in human subjects using [18F]CF and positron emission tomography

  3. Decrease in the number of rat brain dopamine and muscarinic receptors after chronic alcohol intake

    International Nuclear Information System (INIS)

    Syvaelahti, E.K.G.; Hietala, J.; Roeyttae, M.; Groenroos, J.

    1988-01-01

    The effect of 32 weeks' alcohol treatment on the number and affinity of dopamine and muscarinic receptor sites in rat striatum were measured using 3 H-spiperone and 3 H-quinuclidinylbenzilate ( 3 H-QNB) as radioligans. The number of dopamine receptor sites was 38 per cent and the number of muscarinic receptor sites 36 per cent lower in the alcohol group than in control rats. The differences in receptor affinities were less marked. In conclusion, a long-term alcohol intake with rather moderate doses seems to induce a pronounced down-regulation in dopamine and muscarinic receptor systems in rat striatum. (author)

  4. Neurotrophin signaling via TrkB and TrkC receptors promotes the growth of brain tumor-initiating cells.

    Science.gov (United States)

    Lawn, Samuel; Krishna, Niveditha; Pisklakova, Alexandra; Qu, Xiaotao; Fenstermacher, David A; Fournier, Michelle; Vrionis, Frank D; Tran, Nam; Chan, Jennifer A; Kenchappa, Rajappa S; Forsyth, Peter A

    2015-02-06

    Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain

    Directory of Open Access Journals (Sweden)

    Amanda Lorraine Wright

    2012-04-01

    Full Text Available AMPA receptors are comprised of different combinations of GluR1-GluR4 (also known as GluA1-GluA4 and GluR-A to GluR-D subunits. The GluR2 subunit is subject to Q/R site RNA editing by the ADAR2 enzyme, which converts a codon for glutamine (Q, present in the GluR2 gene, to a codon for arginine (R found in the mRNA. AMPA receptors are calcium (Ca2+-permeable if they contain the unedited GluR2(Q subunit or if they lack the GluR2 subunit. While most AMPA receptors in the brain contain the edited GluR2(R subunit and are therefore Ca2+-impermeable, recent evidence suggests that Ca2+-permeable GluR2-lacking AMPA receptors are important in synaptic plasticity and learning. However, the presence of Ca2+-permeable AMPA receptors containing unedited GluR2 leads to excitotoxic cell loss. Recent studies have indicated that RNA editing of GluR2 is deregulated in diseases, such as amyotrophic lateral sclerosis (ALS, as well in acute neurodegenerative conditions, such as ischemia. More recently, studies have investigated the regulation of RNA editing and possible causes for its deregulation during disease. In this review, we will explore the role of GluR2 RNA editing in the healthy and diseased brain and outline new insights into the mechanisms that control this process.

  6. Theobromine-Induced Changes in A1 Purinergic Receptor Gene Expression and Distribution in a Rat Brain Alzheimer's Disease Model.

    Science.gov (United States)

    Mendiola-Precoma, Jesus; Padilla, Karla; Rodríguez-Cruz, Alfredo; Berumen, Laura C; Miledi, Ricardo; García-Alcocer, Guadalupe

    2017-01-01

    Dementia caused by Alzheimer's disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are G protein-coupled. A1 receptors are involved in the inhibition of neurotransmitter release, which could be related to AD. The aim of the present work was to study the effects of a lard-enriched diet (LED) on cognitive and memory processes in adult rats (6 months of age) as well as the effect of theobromine on these processes. The results indicated that the fat-enriched diet resulted in a long-term deterioration in cognitive and memory functions. Increased levels of Aβ protein and IL-1β were also observed in the rats fed with a high-cholesterol diet, which were used to validate the AD animal model. In addition, the results of qPCR and immunohistochemistry indicated a decrease in gene expression and distribution of A1 purinegic receptor, respectively, in the hippocampus of LED-fed rats. Interestingly, theobromine, at both concentrations tested, restored A1 receptor levels and improved cognitive functions and Aβ levels for a dose of 30 mg/L drinking water.

  7. Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice.

    Science.gov (United States)

    Ong, Qi-Rui; Chan, Elizabeth S; Lim, Mei-Li; Cole, Gregory M; Wong, Boon-Seng

    2014-01-17

    Human ApoE4 accelerates memory decline in ageing and in Alzheimer's disease. Although intranasal insulin can improve cognition, this has little effect in ApoE4 subjects. To understand this ApoE genotype-dependent effect, we examined brain insulin signaling in huApoE3 and huApoE4 targeted replacement (TR) mice. At 32 weeks, lower insulin receptor substrate 1 (IRS1) at S636/639 and Akt phosphorylation at T308 were detected in fasting huApoE4 TR mice as compared to fasting huApoE3 TR mice. These changes in fasting huApoE4 TR mice were linked to lower brain glucose content and have no effect on plasma glucose level. However, at 72 weeks of age, these early changes were accompanied by reduction in IRS2 expression, IRS1 phosphorylation at Y608, Akt phosphorylation at S473, and MAPK (p38 and p44/42) activation in the fasting huApoE4 TR mice. The lower brain glucose was significantly associated with higher brain insulin in the aged huApoE4 TR mice. These results show that ApoE4 reduces brain insulin signaling and glucose level leading to higher insulin content.

  8. Oxytocin receptor ligand binding in embryonic tissue and postnatal brain development of the C57BL/6J mouse

    Directory of Open Access Journals (Sweden)

    Elizabeth eHammock

    2013-12-01

    Full Text Available Oxytocin (OXT has drawn increasing attention as a developmentally relevant neuropeptide given its role in the brain regulation of social behavior. It has been suggested that OXT plays an important role in the infant brain during caregiver attachment in nurturing familial contexts, but there is incomplete experimental evidence. Mouse models of OXT system genes have been particularly informative for the role of the OXT system in social behavior, however, the developing brain areas that could respond to ligand activation of the OXT receptor (OXTR have yet to be identified in this species. Here we report new data revealing dynamic ligand-binding distribution of OXTR in the developing mouse brain. Using male and female C57BL/6J mice at postnatal days (P 0, 7, 14, 21, 35, and 60 we quantified OXTR ligand binding in several brain areas which changed across development. Further, we describe OXTR ligand binding in select tissues of the near-term whole embryo at E18.5. Together, these data aid in the interpretation of findings in mouse models of the OXT system and generate new testable hypotheses for developmental roles for OXT in mammalian systems. We discuss our findings in the context of developmental disorders (including autism, attachment biology, and infant physiological regulation.

  9. Imaging for metabotropic glutamate receptor subtype 1 in rat and monkey brains using PET with [18F]FITM.

    Science.gov (United States)

    Yamasaki, Tomoteru; Fujinaga, Masayuki; Maeda, Jun; Kawamura, Kazunori; Yui, Joji; Hatori, Akiko; Yoshida, Yuichiro; Nagai, Yuji; Tokunaga, Masaki; Higuchi, Makoto; Suhara, Tetsuya; Fukumura, Toshimitsu; Zhang, Ming-Rong

    2012-04-01

    In this study, we evaluate the utility of 4-[(18)F]fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]FITM) as a positron emission tomography (PET) ligand for imaging of the metabotropic glutamate receptor subtype 1 (mGluR1) in rat and monkey brains. In vivo distribution of [(18)F]FITM in brains was evaluated by PET scans with or without the mGluR1-selective antagonist (JNJ16259685). Kinetic parameters of monkey PET data were obtained using the two-tissue compartment model with arterial blood sampling. In PET studies in rat and monkey brains, the highest uptake of radioactivity was in the cerebellum, followed by moderate uptake in the thalamus, hippocampus and striatum. The lowest uptake of radioactivity was detected in the pons. These uptakes in all brain regions were dramatically decreased by pre-administration of JNJ16259685. In kinetic analysis of monkey PET, the highest volume of distribution (V(T)) was detected in the cerebellum (V(T) = 11.5). [(18)F]FITM has an excellent profile as a PET ligand for mGluR1 imaging. PET with [(18)F]FITM may prove useful for determining the regional distribution and density of mGluR1 and the mGluR1 occupancy of drugs in human brains.

  10. Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist.

    Science.gov (United States)

    Searle, Graham; Beaver, John D; Comley, Robert A; Bani, Massimo; Tziortzi, Andri; Slifstein, Mark; Mugnaini, Manolo; Griffante, Cristiana; Wilson, Alan A; Merlo-Pich, Emilio; Houle, Sylvain; Gunn, Roger; Rabiner, Eugenii A; Laruelle, Marc

    2010-08-15

    Dopamine D(3) receptors are involved in the pathophysiology of several neuropsychiatric conditions. [(11)C]-(+)-PHNO is a radiolabeled D(2) and D(3) agonist, suitable for imaging the agonist binding sites (denoted D(2HIGH) and D(3)) of these receptors with positron emission tomography (PET). PET studies in nonhuman primates documented that, in vivo, [(11)C]-(+)-PHNO displays a relative selectivity for D(3) compared with D(2HIGH) receptor sites and that the [(11)C]-(+)-PHNO signal is enriched in D(3) contribution compared with conventional ligands such as [(11)C] raclopride. To define the D(3) contribution (f(PHNO)(D3)) to [(11)C]-(+)-PHNO binding potential (BP(ND)) in healthy humans, 52 PET scans were obtained in 19 healthy volunteers at baseline and following oral administration of various doses of the selective D(3) receptor antagonist, GSK598809. The impact of GSK598809 on [(11)C]-(+)-PHNO was regionally selective. In dorsal regions of the striatum, GSK598809 did not significantly affect [(11)C]-(+)-PHNO BP(ND) (f(PHNO)(D3) approximately 0%). Conversely, in the substantia nigra, GSK598809 dose-dependently reduced [(11)C]-(+)-PHNO binding to nonspecific level (f(PHNO)(D3) approximately 100%). In ventral striatum (VST), globus pallidus and thalamus (THA), [(11)C]-(+)-PHNO BP(ND) was attributable to a combination of D(2HIGH) and D(3) receptor sites, with f(PHNO)(D3) of 26%, 67% and 46%, respectively. D(3) receptor binding potential (BP(ND)(D3)) was highest in globus pallidus (1.90) and substantial nigra (1.39), with lower levels in VST (.77) and THA (.18) and negligible levels in dorsal striatum. This study elucidated the pharmacologic nature of the [(11)C]-(+)-PHNO signal in healthy subjects and provided the first quantification of D(3) receptor availability with PET in the living human brain. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  11. Contribution of altered signal transduction associated to glutamate receptors in brain to the neurological alterations of hepatic encephalopathy

    Institute of Scientific and Technical Information of China (English)

    Vicente Felipo

    2006-01-01

    Patients with liver disease may present hepatic encephalopathy (HE), a complex neuropsychiatric syndrome covering a wide range of neurological alterations,including cognitive and motor disturbances. HE reduces the quality of life of the patients and is associated with poor prognosis. In the worse cases HE may lead to coma or death.The mechanisms leading to HE which are not well known are being studied using animal models. The neurological alterations in HE are a consequence of impaired cerebral function mainly due to alterations in neurotransmission. We review here some studies indicating that alterations in neurotransmission associated to different types of glutamate receptors are responsible for some of the cognitive and motor alterations present in HE.These studies show that the function of the signal transduction pathway glutamate-nitric oxide-cGMP associated to the NMDA type of glutamate receptors is impaired in brain in vivo in HE animal models as well as in brain of patients died of HE. Activation of NMDA receptors in brain activates this pathway and increases cGMP. In animal models of HE this increase in cGMP induced by activation of NMDA receptors is reduced,which is responsible for the impairment in learning ability in these animal models. Increasing cGMP by pharmacological means restores learning ability in rats with HE and may be a new therapeutic approach to improve cognitive function in patients with HE.However, it is necessary to previously assess the possible secondary effects.Patients with HE may present psychomotor slowing,hypokinesia and bradykinesia. Animal models of HE also show hypolocomotion. It has been shown in rats with HE that hypolocomotion is due to excessive activation of metabotropic glutamate receptors (mGluRs) in substantia nigra pars reticulata. Blocking mGluR1 in this brain area normalizes motor activity in the rats, suggesting that a similar treatment for patients with HE could be useful to treat psychomotor slowing and

  12. Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot.

    Science.gov (United States)

    Veronese, Mattia; Zanotti-Fregonara, Paolo; Rizzo, Gaia; Bertoldo, Alessandra; Innis, Robert B; Turkheimer, Federico E

    2016-04-15

    PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i

  13. Cloning, phylogeny, and regional expression of a Y5 receptor mRNA in the brain of the sea lamprey (Petromyzon marinus).

    Science.gov (United States)

    Pérez-Fernández, Juan; Megías, Manuel; Pombal, Manuel A

    2014-04-01

    The NPY receptors known as Y receptors are classified into three subfamilies, Y1, Y2, and Y5, and are involved in different physiological functions. The Y5 receptor is the only member of the Y5 subfamily, and it is present in all vertebrate groups, except for teleosts. Both molecular and pharmacological studies show that Y5 receptor is highly conserved during vertebrate evolution. Furthermore, this receptor is widely expressed in the mammalian brain, including the hypothalamus, where it is thought to take part in feeding and homeostasis regulation. Lampreys belong to the agnathan lineage, and they are thought to have branched out between the two whole-genome duplications that occurred in vertebrates. Therefore, they are in a key position for studies on the evolution of gene families in vertebrates. Here we report the cloning, phylogeny, and brain expression pattern of the sea lamprey Y5 receptor. In phylogenetic studies, the lamprey Y5 receptor clusters in a basal position, together with Y5 receptors of other vertebrates. The mRNA of this receptor is broadly expressed in the lamprey brain, being especially abundant in hypothalamic areas. Its expression pattern is roughly similar to that reported for other vertebrates and parallels the expression pattern of the Y1 receptor subtype previously described by our group, as it occurs in mammals. Altogether, these results confirm that a Y5 receptor is present in lampreys, thus being highly conserved during the evolution of vertebrates, and suggest that it is involved in many brain functions, the only known exception being teleosts. Copyright © 2013 Wiley Periodicals, Inc.

  14. Circulating Estradiol Regulates Brain-Derived Estradiol via Actions at GnRH Receptors to Impact Memory in Ovariectomized Rats.

    Science.gov (United States)

    Nelson, Britta S; Black, Katelyn L; Daniel, Jill M

    2016-01-01

    Systemic estradiol treatment enhances hippocampus-dependent memory in ovariectomized rats. Although these enhancements are traditionally thought to be due to circulating estradiol, recent data suggest these changes are brought on by hippocampus-derived estradiol, the synthesis of which depends on gonadotropin-releasing hormone (GnRH) activity. The goal of the current work is to test the hypothesis that peripheral estradiol affects hippocampus-dependent memory through brain-derived estradiol regulated via hippocampal GnRH receptor activity. In the first experiment, intracerebroventricular infusion of letrozole, which prevents the synthesis of estradiol, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory in a radial-maze task. In the second experiment, hippocampal infusion of antide, a long-lasting GnRH receptor antagonist, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory. In the third experiment, hippocampal infusion of GnRH enhanced hippocampus-dependent memory, the effects of which were blocked by letrozole infusion. Results indicate that peripheral estradiol-induced enhancement of cognition is mediated by brain-derived estradiol via hippocampal GnRH receptor activity.

  15. Pharmacological characterization of the dopamine-sensitive adenylate cyclase in cockroach brain: evidence for a distinct dopamine receptor

    International Nuclear Information System (INIS)

    Orr, G.L.; Gole, J.W.D.; Notman, H.J.; Downer, R.G.H.

    1987-01-01

    Dopamine increases cyclic AMP production in crude membrane preparations of cockroach brain with plateaus in cyclic AMP production occurring between 1-10 μM and 10 mM. Maximal production of cyclic AMP is 2.25 fold greater than that of control values. Octopamine also increases cyclic AMP production with a Ka of 1.4 μM and maximal production 3.5 fold greater than that of control. 5-Hydroxytryptamine does not increase cyclic AMP production. The effects of octopamine and dopamine are fully additive. The vertebrate dopamine agonists ADTN and epinine stimulate the dopamine-sensitive adenylate cyclase (AC) with Ka values of 4.5 and 0.6 μM respectively and with maximal effectiveness 1.7 fold greater than that of control. The selective D 2 -dopamine agonist LY-171555 stimulates cyclic AMP production to a similar extent with a Ka of 50 μM. Other dopamine agonists have no stimulatory effects. With the exception of mianserin, 3 H-piflutixol is displaced from brain membranes by dopamine antagonists with an order of potency similar to that observed for the inhibition of dopamine-sensitive AC. The results indicate that the octopamine- and dopamine-sensitive AC in cockroach brain can be distinguished pharmacologically and the dopamine receptors coupled to AC have pharmacological characteristics distinct from vertebrate D 1 - and D 2 -dopamine receptors. 33 references, 3 figures, 2 tables

  16. PCP-induced alterations in cerebral glucose utilization in rat brain: blockade by metaphit, a PCP-receptor-acylating agent

    International Nuclear Information System (INIS)

    Tamminga, C.A.; Tanimoto, K.; Kuo, S.; Chase, T.N.; Contreras, P.C.; Rice, K.C.; Jackson, A.E.; O'Donohue, T.L.

    1987-01-01

    The effects of phencyclidine (PCP) on regional cerebral glucose utilization was determined by using quantitative autoradiography with [ 14 C]-2-deoxyglucose. PCP increased brain metabolism in selected areas of cortex, particularly limbic, and in the basal ganglia and thalamus, whereas the drug decreased metabolism in areas related to audition. These results are consistent with the known physiology of central PCP neurons and may help to suggest brain areas involved in PCP-mediated actions. Moreover, based on the behavioral similarities between PCP psychosis and an acute schizophrenic episode, these data may be relevant to the understanding of schizophrenia. The PCP-receptor-acylating agent, metaphit, blocked most of these PCP actions. In addition, metaphit by itself was found to diminish glucose utilization rather uniformly throughout brain. These results indicate an antagonist effect of metaphit on the PCP system and suggest a widespread action of metaphit, putatively at a PCP-related site, possibly in connection with the N-methyl-D-aspartate (NMDA) receptor

  17. The brain 5-HT4 receptor binding is down-regulated in the Flinders Sensitive Line depression model and in response to paroxetine administration

    DEFF Research Database (Denmark)

    Licht, Cecilie Löe; Marcussen, Anders Bue; Wegener, Gregers

    2009-01-01

    The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiography....... In the Flinders Sensitive Line, the 5-HT(4) receptor and 5-HT transporter binding were decreased in the dorsal and ventral hippocampus, and the changes in binding were directly correlated within the dorsal hippocampus. Chronic but not acute paroxetine administration caused a 16-47% down-regulation of 5-HT(4......) receptor binding in all regions evaluated including the basal ganglia and hippocampus, while 5-HT depletion increased the 5-HT(4) receptor binding in the dorsal hippocampus, hypothalamus, and lateral globus pallidus. In comparison, the 5-HT(2A) receptor binding was decreased in the frontal and cingulate...

  18. Molecular, pharmacological, and signaling properties of octopamine receptors from honeybee (Apis mellifera) brain.

    Science.gov (United States)

    Balfanz, Sabine; Jordan, Nadine; Langenstück, Teresa; Breuer, Johanna; Bergmeier, Vera; Baumann, Arnd

    2014-04-01

    G protein-coupled receptors are important regulators of cellular signaling processes. Within the large family of rhodopsin-like receptors, those binding to biogenic amines form a discrete subgroup. Activation of biogenic amine receptors leads to transient changes of intracellular Ca²⁺-([Ca²⁺](i)) or 3',5'-cyclic adenosine monophosphate ([cAMP](i)) concentrations. Both second messengers modulate cellular signaling processes and thereby contribute to long-lasting behavioral effects in an organism. In vivo pharmacology has helped to reveal the functional effects of different biogenic amines in honeybees. The phenolamine octopamine is an important modulator of behavior. Binding of octopamine to its receptors causes elevation of [Ca²⁺](i) or [cAMP](i). To date, only one honeybee octopamine receptor that induces Ca²⁺ signals has been molecularly and pharmacologically characterized. Here, we examined the pharmacological properties of four additional honeybee octopamine receptors. When heterologously expressed, all receptors induced cAMP production after binding to octopamine with EC₅₀(s) in the nanomolar range. Receptor activity was most efficiently blocked by mianserin, a substance with antidepressant activity in vertebrates. The rank order of inhibitory potency for potential receptor antagonists was very similar on all four honeybee receptors with mianserin > cyproheptadine > metoclopramide > chlorpromazine > phentolamine. The subroot of octopamine receptors activating adenylyl cyclases is the largest that has so far been characterized in arthropods, and it should now be possible to unravel the contribution of individual receptors to the physiology and behavior of honeybees. © 2013 International Society for Neurochemistry.

  19. Hydrolysis of cytectrene marked by the technetium 99m by acetylcholinesterase in the rat brain and confirmation of fixing the cytectrene on brain receptors

    International Nuclear Information System (INIS)

    Mejri, N.; Barhoumi, M.C.; Mekni, A.; Coulais, Y.; Amri, M.; Masmoudi, O.; Saidi, M

    2008-01-01

    Alzheimer's disease is a degenerative neurological disorder that causes progressive and irreversible loss of mental functions. It is the most common form of dementia and is characterized by a decrease in serotonergic neurons that carry the 5HT1A receptors. We showed that the use of cytectrene for the quantitative measurement of the activity of the Acetylcholinesterase in the brain depends on the rate of hydrolysis and the enzymatic specificity. The results showed that the cytectrene can be used as a substrate for a precise and quantitative determination of the activity of this enzyme. We have made hippocampal and cortical neuron cultures in the brain from young rats. After the differentiation of these neurons, some cell cultures are incubated with 8 OH DPAT, a receptor 5HT1A agonist of the serotonin, which are located on the surface of neurons. The neurons are then incubated with a molecule marked with radioactive technetium 99m Tc. These neurons are crushed and radioactivity is read. The results show that for growing neurons in the hippocampus, we have levels of radioactivity cells treated with agonist, below the level of radioactivity of cells treated with the radioactive molecules. The cortical neurons show the same level of radioactivity in the cells treated with agonist for cells treated only with the molecule marked. Our results show a decrease of fixing the molecule marked on 5HT1A receptor neurons in the hippocampus compared to neurons in the cortex. This work will enable us to prove the decrease of neurons in neuronal diseases and to make the diagnosis of these diseases. (author)

  20. Molecular cloning of a functional allatostatin gut/brain receptor and an allatostatin preprohormone from the silkworm Bombyx mori

    DEFF Research Database (Denmark)

    Secher, Thomas; Lenz, C; Cazzamali, G

    2001-01-01

    in the DAR-1 and DAR-2 genes, showing that the three receptors are not only structurally but also evolutionarily related. Furthermore, we have cloned a Bombyx allatostatin preprohormone that contains eight different A-type allatostatins. Chinese hamster ovary cells permanently transfected with BAR DNA react......The cockroach-type or A-type allatostatins are inhibitory insect neuropeptides with the C-terminal sequence Tyr/Phe-X-Phe-Gly-Leu-NH(2). Here, we have cloned an A-type allatostatin receptor from the silkworm Bombyx mori (BAR). BAR is 361 amino acid residues long, has seven transmembrane domains....... Northern blots and quantitative reverse transcriptase-polymerase chain reaction of different larval tissues show that BAR mRNA is mainly expressed in the gut and to a much lesser extent in the brain. To our knowledge, this is the first report on the molecular cloning and functional expression of an insect...

  1. The effect of ZMS on the coupling of muscarinic receptor to G-proteins activation in rat brain

    International Nuclear Information System (INIS)

    Fang Cailong; Hu Yaer; Gao Ruxue; Xia Zongqin

    1999-01-01

    The carbachol-stimulated [ 35 S]GTP γ S binding method was used to observe the effect of ZMS, an active component from Zhimu, on the coupling of M-receptor to G-protein. the effect of ZMS on the ability of learning and memory in aged rats was also observed. It was shown that the carbachol-stimulated elevation of [ 35 S]GTPγS binding was significantly decreased in aged rats as compared with young rats. The carbachol-induced [ 35 S]STPγS binding showed that administration of ZMS at median or high dose have a definite elevation effect on the coupling activity of M-receptors to G-protein in brain, and this elevation was accompanied by an improvement of learning and memory ability

  2. Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications

    Directory of Open Access Journals (Sweden)

    Andreas eStengel

    2013-01-01

    Full Text Available Somatostatin is an important modulator of neurotransmission in the central nervous system and acts as a potent inhibitor of hormone and exocrine secretion and regulator of cell proliferation in the periphery. These pleiotropic actions occur through interaction with five G-protein coupled somatostatin receptor subtypes (sst1-5 that are widely expressed in the brain and peripheral organs. The characterization of somatostatin’s effects can be investigated by pharmacological or genetic approaches using newly developed selective sst agonists and antagonists and mice lacking specific sst subtypes. Recent evidence points towards a divergent action of somatostatin in the brain and in the periphery to regulate circulating levels of ghrelin, an orexigenic hormone produced by the endocrine X/A-like cells in the gastric mucosa. Somatostatin interacts with the sst2 in the brain to induce an increase in basal ghrelin plasma levels and counteracts the visceral stress-related decrease in circulating ghrelin in rats. By contrast, stimulation of peripheral somatostatin-sst2 signaling results in the inhibition of basal ghrelin release and mediates the postoperative decrease in circulating ghrelin in rats. The peripheral sst2-mediated reduction of plasma ghrelin is likely to involve a paracrine action of D-cell derived somatostatin acting on sst2 bearing X/A-like ghrelin cells in the gastric mucosa. The other member of the somatostatin family, named cortistatin, in addition to binding to sst1-5 also directly interacts with the ghrelin receptor and therefore may simultaneously modulate ghrelin release and actions at target sites bearing ghrelin receptors representing a link between the ghrelin and somatostatin systems.

  3. The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair.

    Directory of Open Access Journals (Sweden)

    Davide Lecca

    Full Text Available Deciphering the mechanisms regulating the generation of new neurons and new oligodendrocytes, the myelinating cells of the central nervous system, is of paramount importance to address new strategies to replace endogenous damaged cells in the adult brain and foster repair in neurodegenerative diseases. Upon brain injury, the extracellular concentrations of nucleotides and cysteinyl-leukotrienes (cysLTs, two families of endogenous signaling molecules, are markedly increased at the site of damage, suggesting that they may act as "danger signals" to alert responses to tissue damage and start repair. Here we show that, in brain telencephalon, GPR17, a recently deorphanized receptor for both uracil nucleotides and cysLTs (e.g., UDP-glucose and LTD(4, is normally present on neurons and on a subset of parenchymal quiescent oligodendrocyte precursor cells. We also show that induction of brain injury using an established focal ischemia model in the rodent induces profound spatiotemporal-dependent changes of GPR17. In the lesioned area, we observed an early and transient up-regulation of GPR17 in neurons expressing the cellular stress marker heat shock protein 70. Magnetic Resonance Imaging in living mice showed that the in vivo pharmacological or biotechnological knock down of GPR17 markedly prevents brain infarct evolution, suggesting GPR17 as a mediator of neuronal death at this early ischemic stage. At later times after ischemia, GPR17 immuno-labeling appeared on microglia/macrophages infiltrating the lesioned area to indicate that GPR17 may also acts as a player in the remodeling of brain circuitries by microglia. At this later stage, parenchymal GPR17+ oligodendrocyte progenitors started proliferating in the peri-injured area, suggesting initiation of remyelination. To confirm a specific role for GPR17 in oligodendrocyte differentiation, the in vitro exposure of cortical pre-oligodendrocytes to the GPR17 endogenous ligands UDP-glucose and LTD(4

  4. HMGB1 Contributes to the Expression of P-Glycoprotein in Mouse Epileptic Brain through Toll-Like Receptor 4 and Receptor for Advanced Glycation End Products.

    Directory of Open Access Journals (Sweden)

    Yan Chen

    Full Text Available The objective of the present study was to investigate the role of high-mobility group box-1 (HMGB1 in the seizure-induced P-glycoprotein (P-gp overexpression and the underlying mechanism. Kainic acid (KA-induced mouse seizure model was used for in vivo experiments. Male C57BL/6 mice were divided into four groups: normal saline control (NS group, KA-induced epileptic seizure (EP group, and EP group pretreated with HMGB1 (EP+HMGB1 group or BoxA (HMGB1 antagonist, EP+BoxA group. Compared to the NS group, increased levels of HMGB1 and P-gp in the brain were observed in the EP group. Injection of HMGB1 before the induction of KA further increased the expression of P-gp while pre-treatment with BoxA abolished this up-regulation. Next, the regulatory role of HMGB1 and its potential involved signal pathways were investigated in mouse microvascular endothelial bEnd.3 cells in vitro. Cells were treated with HMGB1, HMGB1 plus lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS [toll-like receptor 4 (TLR4 antagonist], HMGB1 plus FPS-ZM1 [receptor for advanced glycation end products (RAGE inhibitor], HMGB1 plus SN50 [nuclear factor-kappa B (NF-κB inhibitor], or vehicle. Treatment with HMGB1 increased the expression levels of P-gp, TLR4, RAGE and the activation of NF-κB in bEnd.3 cells. These effects were inhibited by the pre-treatment with either LPS-RS or FPS-ZM1, and were abolished by the pre-treatment of SN50 or a combination treatment of both LPS-RS and FPS-ZM1. Luciferase reporter assays showed that exogenous expression of NF-κB p65 increased the promoter activity of multidrug resistance 1a (P-gp-encoding gene in endothelial cells. These data indicate that HMGB1 contributes to the overexpression of P-gp in mouse epileptic brain tissues via activation of TLR4/RAGE receptors and the downstream transcription factor NF-κB in brain microvascular endothelial cells.

  5. Unsurmountable antagonism of brain 5-hydroxytryptamine2 receptors by (+)-lysergic acid diethylamide and bromo-lysergic acid diethylamide.

    Science.gov (United States)

    Burris, K D; Sanders-Bush, E

    1992-11-01

    Lysergic acid diethylamide (LSD) and its structural analogue 2-bromo-lysergic acid diethylamide (BOL) act as unsurmountable antagonists of serotonin-elicited contractions in smooth muscle preparations. Two different models, allosteric and kinetic, have been invoked to explain these findings. The present studies investigate the mechanism of antagonism of brain 5-hydroxytryptamine (5HT)2 receptors, utilizing cells transfected with 5HT2 receptor cDNA cloned from rat brain. A proximal cellular response, phosphoinositide hydrolysis, was examined in order to minimize possible postreceptor effects. Even though LSD behaved as a partial agonist and BOL as a pure antagonist, both drugs blocked the effect of serotonin in an unsurmountable manner, i.e., increasing concentrations of serotonin could not overcome the blocking effect of LSD or BOL. Radioligand binding studies showed that preincubation of membranes with either LSD or BOL reduced the density of [3H]ketanserin binding sites, suggesting that the drugs bind tightly to the 5HT2 receptor and are not displaced during the binding assay. Two additional experiments supported this hypothesis. First, the off-rate of [3H] LSD was slow (20 min), relative to that of [3H]ketanserin (approximately 4 min). Second, when the length of incubation with [3H]ketanserin was increased to 60 min, the LSD-induced decrease in Bmax was essentially eliminated. The possibility that LSD and BOL decrease [3H]ketanserin binding by interacting with an allosteric site was rejected, because neither drug altered the rate of dissociation of [3H]ketanserin. The most parsimonious interpretation of these results is that unsurmountable antagonism reflects prolonged occupancy of the receptor by slowly reversible antagonists.

  6. Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain

    International Nuclear Information System (INIS)

    Ali, S.F.; Newport, G.D.; Scallet, A.C.; Gee, K.W.; Paule, M.G.; Brown, R.M.; Slikker, W. Jr.

    1989-01-01

    THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the [35S]TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of [35S]TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects

  7. Metabolic rate in different rat brain areas during seizures induced by a specific delta opiate receptor agonist.

    Science.gov (United States)

    Haffmans, J; De Kloet, R; Dzoljic, M R

    1984-06-04

    The glucose utilization during specific delta opiate agonist-induced epileptiform phenomena, determined by the [14C]2-deoxyglucose technique (2-DG), was examined in various rat brain areas at different time intervals. The peak in EEG spiking response and the most intensive 2-DG uptake occurred 5 min after intraventricular (i.v.t.) administration of the delta opiate receptor agonist. The most pronounced 2-DG uptake at this time interval can be observed in the subiculum, including the CA1 hippocampal area, frontal cortex and central amygdala. A general decrease of glucose consumption, compared to control values, is observed after 10 min, in all regions, with exception of the subiculum. Since functional activity and 2-DG uptake are correlated, we suggest that the subiculum and/or CA1 area, are probably the brain regions most involved in the enkephalin-induced epileptic phenomena.

  8. Effects of trihexyphenidyl and L-dopa on brain muscarinic cholinergic receptor binding measured by positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Shinotoh, H; Asahina, M; Hirayama, K [Dept. of Neurology, School of Medicine, Chiba Univ., Chiba (Japan); Inoue, O; Suhara, T; Tateno, Y [Division of Clinical Research, National Inst. of Radiological Sciences, Chiba (Japan)

    1994-01-01

    The effects of pharmacological intervention on brain muscarinic cholinergic receptor (mAChR) binding were assessed in seven patients with Parkinson's disease by positron emission tomography and carbon-11 labelled N-methyl-4-piperidyl benzilate ([[sup 11]C]NMPB). [[sup 11]C]NMPB was injected twice, approximately 2 hours apart, in each patient, to assess the effect of single doses of 4 mg of trihexyphenidyl (n=5) or 400 mg of L-dopa with 57 mg of benserazide (n=2) on the binding parameter of mAChRs (K[sub 3]). There was a mean 28% inhibition of K[sub 3] values in the brain in the presence of trihexyphenidyl, which was assumed to reflect mAChR occupancy. No significant change in K[sub 3] was observed in the presence of L-dopa. This study demonstrates the feasibility of measuring mAChR occupancy by an anticholinergic medication with PET.

  9. Simplified PET measurement for evaluating histamine H1 receptors in human brains using [11C]doxepin

    International Nuclear Information System (INIS)

    Mochizuki, Hideki; Kimura, Yuichi; Ishii, Kenji; Oda, Keiichi; Sasaki, Toru; Tashiro, Manabu; Yanai, Kazuhiko; Ishiwata, Kiichi

    2004-01-01

    The aim of this study was to develop simplified positron emission tomography measurement using [ 11 C]doxepin ([ 11 C]DOX) to evaluate histamine H 1 receptors (H1Rs) in human brains. We evaluated the correlation between the distribution volume (DV) of [ 11 C]DOX, estimated quantitatively with a two-compartment model, and the [ 11 C]DOX uptake obtained at various time intervals and normalized using the metabolite-corrected plasma radioactivity. We found that the static 70- to 90-min images normalized using the plasma radioactivity at 10 min postinjection reflected the DV of [ 11 C]DOX-H1R binding

  10. Minocycline exacerbates apoptotic neurodegeneration induced by the NMDA receptor antagonist MK-801 in the early postnatal mouse brain.

    Science.gov (United States)

    Inta, Ioana; Vogt, Miriam A; Vogel, Anne S; Bettendorf, Markus; Gass, Peter; Inta, Dragos

    2016-10-01

    NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.

  11. Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: Implications for its efficacy in bipolar disorder

    Science.gov (United States)

    Ramadan, Epolia; Basselin, Mireille; Rao, Jagadeesh S.; Chang, Lisa; Chen, Mei; Ma, Kaizong; Rapoport, Stanley I.

    2011-01-01

    An upregulated brain arachidonic acid (AA) cascade and a hyperglutamatergic state characterize bipolar disorder (BD). Lamotrigine (LTG), a mood stabilizer approved for treating BD, is reported to interfere with glutamatergic neurotransmission involving N-methyl-D-aspartate receptors (NMDARs). NMDARs allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 (cPLA2) to release arachidonic acid (AA) from membrane phospholipid. We hypothesized that LTG, like other approved mood stabilizers, would reduce NMDAR-mediated AA signaling in rat brain. An acute subconvulsant dose of NMDA (25 mg/kg) or saline was administered intraperitoneally to unanesthetized rats that had been treated p.o. daily for 42 days with vehicle or a therapeutically relevant dose of LTG (10 mg/kg/.d). Regional brain AA incorporation coefficients k* and rates Jin, AA signals, were measured using quantitative autoradiography after intravenous [1-14C]AA infusion, as were other AA cascade markers. In chronic vehicle-treated rats, acute NMDA compared to saline increased k* and Jin in widespread regions of the brain, as well as prostaglandin (PG)E2 and thromboxane B2 concentrations. Chronic LTG treatment compared to vehicle reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA binding activity of the COX-2 transcription factor, NF-κB. Pretreatment with chronic LTG blocked the acute NMDA effects on AA cascade markers. In summary, chronic LTG like other mood stabilizers blocks NMDA-mediated signaling involving the AA metabolic cascade. Since markers of the AA cascade and of NMDAR signaling are up-regulated in the postmortem BD brain, mood stabilizers generally may be effective in BD by dampening NMDAR signalling and the AA cascade. PMID:21733229

  12. Solid lipid nanoparticles carrying chemotherapeutic drug across the blood-brain barrier through insulin receptor-mediated pathway.

    Science.gov (United States)

    Kuo, Yung-Chih; Shih-Huang, Chun-Yuan

    2013-09-01

    Carmustine (BCNU)-loaded solid lipid nanoparticles (SLNs) were grafted with 83-14 monoclonal antibody (MAb) (83-14 MAb/BCNU-SLNs) and applied to the brain-targeting delivery. Human brain-microvascular endothelial cells (HBMECs) incubated with 83-14 MAb/BCNU-SLNs were stained to demonstrate the interaction between the nanocarriers and expressed insulin receptors (IRs). The results revealed that the particle size of 83-14 MAb/BCNU-SLNs decreased with an increasing weight percentage of Dynasan 114 (DYN). Storage at 4 °C for 6 weeks slightly deformed the colloidal morphology. In addition, poloxamer 407 on 83-14 MAb/BCNU-SLNs induced cytotoxicity to RAW264.7 cells and inhibited phagocytosis by RAW264.7 cells. An increase in the weight percentage of DYN from 0% to 67% slightly reduced the viability of RAW264.7 cells and promoted phagocytosis. Moreover, the transport ability of 83-14 MAb/BCNU-SLNs across the blood-brain barrier (BBB) in vitro enhanced with an increasing weight percentage of Tween 80. 83-14 MAb on MAb/BCNU-SLNs stimulated endocytosis by HBMECs via IRs and enhanced the permeability of BCNU across the BBB. 83-14 MAb/BCNU-SLNs can be a promising antitumor drug delivery system for transporting BCNU to the brain.

  13. Characterization of [(11)C]Cimbi-36 as an agonist PET radioligand for the 5-HT(2A) and 5-HT(2C) receptors in the nonhuman primate brain

    DEFF Research Database (Denmark)

    Finnema, Sjoerd J; Stepanov, Vladimir; Ettrup, Anders

    2014-01-01

    a more meaningful assessment of available receptors than antagonist radioligands. In the current study we characterized [(11)C]Cimbi-36 receptor binding in the primate brain. On five experimental days, a total of 14 PET measurements were conducted in three female rhesus monkeys. On each day, PET...... agonist radioligand suitable for examination of 5-HT2A receptors in the cortical regions and of 5-HT2C receptors in the choroid plexus of the primate brain....

  14. [On the role of selective silencer Freud-1 in the regulation of the brain 5-HT(1A) receptor gene expression].

    Science.gov (United States)

    Naumenko, V S; Osipova, D V; Tsybko, A S

    2010-01-01

    Selective 5-HT(1A) receptor silencer (Freud-1) is known to be one of the main factors for transcriptional regulation of brain serotonin 5-HT(1A) receptor. However, there is a lack of data on implication of Freud-1 in the mechanisms underlying genetically determined and experimentally altered 5-HT(1A) receptor system state in vivo. In the present study we have found a difference in the 5-HT(1A) gene expression in the midbrain of AKR and CBA inbred mouse strains. At the same time no distinction in Freud-1 expression was observed. We have revealed 90.3% of homology between mouse and rat 5-HT(1A) receptor DRE-element, whereas there was no difference in DRE-element sequence between AKR and CBA mice. This indicates the absence of differences in Freud-1 binding site in these mouse strains. In the model of 5-HT(1A) receptor desensitization produced by chronic 5-HT(1A) receptor agonist administration, a significant reduction of 5-HT(1A) receptor gene expression together with considerable increase of Freud-1 expression were found. These data allow us to conclude that the selective silencer of 5-HT(1A) receptor, Freud-1, is involved in the compensatory mechanisms that modulate the functional state of brain serotonin system, although it is not the only factor for 5-HT(1A) receptor transcriptional regulation.

  15. The glucocorticoid receptor in the limbic system of the human brain

    NARCIS (Netherlands)

    Wang, Qian

    2016-01-01

    Glucocorticoid hormones (GCs) are important mediators of the stress response in mammals including humans. GCs are released from the adrenal in response to stress and affect numerous processes in the body and brain. Their levels are controlled via negative feedback exerted by GC binding to brain

  16. Immunohistochemical Localization of AT1a, AT1b, and AT2 Angiotensin II Receptor Subtypes in the Rat Adrenal, Pituitary, and Brain with a Perspective Commentary

    Directory of Open Access Journals (Sweden)

    Courtney Premer

    2013-01-01

    Full Text Available Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors: AT1a, AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealed AT1a and AT2 receptors in adrenal zona glomerulosa and medulla. AT1b immunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural immunogold labeling for the AT1a receptor in glomerulosa and medullary cells localized it to plasma membrane, endocytic vesicles, multivesicular bodies, and the nucleus. AT1b and AT2, but not AT1a, immunofluorescence was observed in the anterior pituitary. Stellate cells were AT1b positive while ovoid cells were AT2 positive. In the brain, neurons were AT1a, AT1b, and AT2 positive, but glia was only AT1b positive. Highest levels of AT1a, AT1b, and AT2 receptor immunofluorescence were in the subfornical organ, median eminence, area postrema, paraventricular nucleus, and solitary tract nucleus. These studies complement those employing different techniques to characterize Ang II receptors.

  17. Functional responses of pre- and postsynaptic dopamine D2 receptors in rat brain striatum

    OpenAIRE

    Ma, Guofen

    2014-01-01

    El sistema dopaminèrgic has estat molt estudiat en els darrers anys, principalment degut a la seva implicació en diverses patologies com la malaltia de Parkinson, la esquizofrènia o la síndrome de Tourette, així com també en l'abús de drogues. S'han descrit cinc subtipus de receptors per la dopamina (DA), tots els quals pertanyen a la família de receptors acoblats a proteïnes G (GPCRs). D'aquests cinc subtipus, els receptors D2 son la diana principal dels antipsicòtics (antagonistes) i també ...

  18. Removal of reproductive suppression reveals latent sex differences in brain steroid hormone receptors in naked mole-rats, Heterocephalus glaber.

    Science.gov (United States)

    Swift-Gallant, Ashlyn; Mo, Kaiguo; Peragine, Deane E; Monks, D Ashley; Holmes, Melissa M

    2015-01-01

    Naked mole-rats are eusocial mammals, living in large colonies with a single breeding female and 1-3 breeding males. Breeders are socially dominant, and only the breeders exhibit traditional sex differences in circulating gonadal steroid hormones and reproductive behaviors. Non-reproductive subordinates also fail to show sex differences in overall body size, external genital morphology, and non-reproductive behaviors. However, subordinates can transition to breeding status if removed from their colony and housed with an opposite-sex conspecific, suggesting the presence of latent sex differences. Here, we assessed the expression of steroid hormone receptor and aromatase messenger RNA (mRNA) in the brains of males and females as they transitioned in social and reproductive status. We compared in-colony subordinates to opposite-sex subordinate pairs that were removed from their colony for either 1 day, 1 week, 1 month, or until they became breeders (i.e., produced a litter). Diencephalic tissue was collected and mRNA of androgen receptor (Ar), estrogen receptor alpha (Esr1), progesterone receptor (Pgr), and aromatase (Cyp19a1) was measured using qPCR. Testosterone, 17β-estradiol, and progesterone from serum were also measured. As early as 1 week post-removal, males exhibited increased diencephalic Ar mRNA and circulating testosterone, whereas females had increased Cyp19a1 mRNA in the diencephalon. At 1 month post-removal, females exhibited increased 17β-estradiol and progesterone. The largest changes in steroid hormone receptors were observed in breeders. Breeding females had a threefold increase in Cyp19a1 and fivefold increases in Esr1 and Pgr, whereas breeding males had reduced Pgr and increased Ar. These data demonstrate that sex differences in circulating gonadal steroids and hypothalamic gene expression emerge weeks to months after subordinate animals are removed from reproductive suppression in their home colony.

  19. 5-HT4-receptors modulate induction of long-term depression but not potentiation at hippocampal output synapses in acute rat brain slices.

    Directory of Open Access Journals (Sweden)

    Matthias Wawra

    Full Text Available The subiculum is the principal target of CA1 pyramidal cells and mediates hippocampal output to various cortical and subcortical regions of the brain. The majority of subicular pyramidal cells are burst-spiking neurons. Previous studies indicated that high frequency stimulation in subicular burst-spiking cells causes presynaptic NMDA-receptor dependent long-term potentiation (LTP whereas low frequency stimulation induces postsynaptic NMDA-receptor-dependent long-term depression (LTD. In the present study, we investigate the effect of 5-hydroxytryptamine type 4 (5-HT4 receptor activation and blockade on both forms of synaptic plasticity in burst-spiking cells. We demonstrate that neither activation nor block of 5-HT4 receptors modulate the induction or expression of LTP. In contrast, activation of 5-HT4 receptors facilitates expression of LTD, and block of the 5-HT4 receptor prevents induction of short-term depression and LTD. As 5-HT4 receptors are positively coupled to adenylate cyclase 1 (AC1, 5-HT4 receptors might modulate PKA activity through AC1. Since LTD is blocked in the presence of 5-HT4 receptor antagonists, our data are consistent with 5-HT4 receptor activation by ambient serotonin or intrinsically active 5-HT4 receptors. Our findings provide new insight into aminergic modulation of hippocampal output.

  20. Muscarinic receptor plasticity in the brain of senescent rats: down-regulation after repeated administration of diisopropyl fluorophosphate

    International Nuclear Information System (INIS)

    Pintor, A.; Fortuna, S.; Volpe, M.T.; Michalek, H.

    1988-01-01

    Potential age-related differences in the response of Fischer 344 rats to subchronic treatment with diisopropylfluorophosphate (DFP) were evaluated in terms of brain cholinesterase (ChE) inhibition and muscarinic receptor sites. Male 3- and 24-month old rats were sc injected with sublethal doses of DFP for 2 weeks and killed 48 hrs after the last treatment. In the cerebral cortex, hippocampus and striatum of control rats a significant age-related reduction of ChE and of maximum number of 3 H-QNB binding sites (Bmax) was observed. The administration of DFP to senescent rats resulted in more pronounced and longer lasting syndrome of cholinergic stimulation, with marked body weight loss and 60% mortality. The percentage inhibition of brain ChE induced by DFP did not differ between young and senescent rats. As expected, in young rats DFP caused a significant decrease of Bmax, which in the cerebral cortex reached about 40%. In the surviving senescent rats, the percentage decrease of Bmax due to DFP with respect to age-matched controls was very similar to that of young animals, especially in the cerebral cortex. Thus there is great variability in the response of aged rats to DFP treatment, from total failure of adaptive mechanisms resulting in death to considerable muscarinic receptor plasticity

  1. Muscarinic receptor plasticity in the brain of senescent rats: down-regulation after repeated administration of diisopropyl fluorophosphate

    Energy Technology Data Exchange (ETDEWEB)

    Pintor, A.; Fortuna, S.; Volpe, M.T.; Michalek, H.

    1988-01-01

    Potential age-related differences in the response of Fischer 344 rats to subchronic treatment with diisopropylfluorophosphate (DFP) were evaluated in terms of brain cholinesterase (ChE) inhibition and muscarinic receptor sites. Male 3- and 24-month old rats were sc injected with sublethal doses of DFP for 2 weeks and killed 48 hrs after the last treatment. In the cerebral cortex, hippocampus and striatum of control rats a significant age-related reduction of ChE and of maximum number of /sup 3/H-QNB binding sites (Bmax) was observed. The administration of DFP to senescent rats resulted in more pronounced and longer lasting syndrome of cholinergic stimulation, with marked body weight loss and 60% mortality. The percentage inhibition of brain ChE induced by DFP did not differ between young and senescent rats. As expected, in young rats DFP caused a significant decrease of Bmax, which in the cerebral cortex reached about 40%. In the surviving senescent rats, the percentage decrease of Bmax due to DFP with respect to age-matched controls was very similar to that of young animals, especially in the cerebral cortex. Thus there is great variability in the response of aged rats to DFP treatment, from total failure of adaptive mechanisms resulting in death to considerable muscarinic receptor plasticity.

  2. Successful combination immunotherapy of anti-gamma aminobutyric acid (GABA)A receptor antibody-positive encephalitis with extensive multifocal brain lesions.

    Science.gov (United States)

    Fukami, Yuki; Okada, Hiroaki; Yoshida, Mari; Yamaguchi, Keiji

    2017-08-31

    A 78-year old woman who presented with akinetic mutism was admitted to our hospital. Brain MRI showed multifocal increased T 2 /FLAIR signal with extensive cortical-subcortical involvement. We suspected autoimmune encephalitis and the patient received methylprednisolone pulse. Her conscious level gradually recovered, but later relapsed again and presented with refractory status epilepticus. We treated her with intravenous immunoglobulin, plasma exchange and pulsed cyclophosphamide, with satisfactory response. A brain biopsy showed perivascular lymphocytic infiltrates and reactive gliosis. Anti-gamma aminobutyric acid (GABA) A receptor antibodies test came back to be positive after her recovery, and the diagnosis of anti-GABA A receptor antibody-positive encephalitis was made. This is a very rare case where brain biopsies were performed in a patient with anti-GABA A receptor antibody-positive encephalitis.

  3. Toll-like receptors and cytokines in the brain and in spleen of dogs with visceral leishmaniosis.

    Science.gov (United States)

    Grano, Fernanda G; Dos S Silva, José Eduardo; Melo, Guilherme D; de Souza, Milena S; Lima, Valéria M F; Machado, Gisele F

    2018-04-15

    Visceral leishmaniosis (VL) is a multisystem disease that affects domestic dogs and can have several clinical manifestations, including some rare reports of neurological clinical signs, or it may remain asymptomatic, depending on the individual immune response against the Leishmania parasite. VL involves immune system sensors, such as the Toll-like receptors (TLRs), that are related to innate immunity and inflammation. Previously, we have reported the presence of brain inflammation in infected dogs. Here, we investigated the gene expression profile of TLRs 1-10 in the brain and the spleen of infected dogs, along with the production of proinflammatory cytokines (TNF-α, IFN-γ, IL-1β and IL-6) with the aim of explaining the origin of brain inflammation. The gene expression of TLRs has varied according to the tissue evaluated. In the brain, TLR-4 was only up-regulated in a small subpopulation of infected dogs, while in the spleen, we detected an increase in TLR-5 and TLR-9 transcripts, as well as a reduction in TLRs 2-4 and TLR-10. All cytokines except IL-6 were detected in infected dogs. Moreover, we detected Leishmania DNA in all infected dogs in both tissues evaluated. In the histopathological analysis, we observed a predominance of lymphoplasmacytic infiltrate, mainly in leptomeninges and choroid plexuses, ranging from mild to intense. This study provides the first insight into the TLRs profile in the brain and the spleen during canine VL and provides support to confirm the involvement of sensors of the innate immune system sensors against L. infantum parasites. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Brain catalase activity inhibition as well as opioid receptor antagonism increases ethanol-induced HPA axis activation.

    Science.gov (United States)

    Pastor, Raúl; Sanchis-Segura, Carles; Aragon, Carlos M G

    2004-12-01

    Growing evidence indicates that brain catalase activity is involved in the psychopharmacological actions of ethanol. Recent data suggest that participation of this enzymatic system in some ethanol effects could be mediated by the endogenous opioid system. The present study assessed whether brain catalase has a role in ethanol-induced activation of the HPA axis, a neuroendocrine system modulated by the endogenous opioid neurotransmission. Swiss male mice received an intraperitoneal injection of the catalase inhibitor 3-amino-1,2,4-triazole (AT; 0-1 g/kg), and 0 to 20 hr after this administration, animals received an ethanol (0-4 g/kg; intraperitoneally) challenge. Thirty, 60, or 120 min after ethanol administration, plasma corticosterone levels were determined immunoenzymatically. In addition, we tested the effects of 45 mg/kg of cyanamide (another catalase inhibitor) and 0 to 2 mg/kg of naltrexone (nonselective opioid receptor antagonist) on ethanol-induced enhancement in plasma corticosterone values. The present study revealed that AT boosts ethanol-induced increase in plasma corticosterone levels in a dose- and time-dependent manner. However, it did not affect corticosterone values when measured after administration of saline, cocaine (4 mg/kg, intraperitoneally), or morphine (30 mg/kg, intraperitoneally). The catalase inhibitor cyanamide (45 mg/kg, intraperitoneally) also increased ethanol-related plasma corticosterone levels. These effects of AT and cyanamide on ethanol-induced corticosterone values were observed under treatment conditions that decreased significantly brain catalase activity. Indeed, a significant correlation between effects of catalase manipulations on both variables was found. Finally, we found that the administration of naltrexone enhanced the levels of plasma corticosterone after the administration of saline or ethanol. This study shows that the inhibition of brain catalase increases ethanol-induced plasma corticosterone levels. Results are

  5. Effects of acute restraint-induced stress on glucocorticoid receptors and brain-derived neurotrophic factor after mild traumatic brain injury.

    Science.gov (United States)

    Griesbach, G S; Vincelli, J; Tio, D L; Hovda, D A

    2012-05-17

    We have previously reported that experimental mild traumatic brain injury results in increased sensitivity to stressful events during the first post-injury weeks, as determined by analyzing the hypothalamic-pituitary-adrenal (HPA) axis regulation following restraint-induced stress. This is the same time period when rehabilitative exercise has proven to be ineffective after a mild fluid-percussion injury (FPI). Here we evaluated effects of stress on neuroplasticity. Adult male rats underwent either an FPI or sham injury. Additional rats were only exposed to anesthesia. Rats were exposed to 30 min of restraint stress, followed by tail vein blood collection at post-injury days (PID) 1, 7, and 14. The response to dexamethasone (DEX) was also evaluated. Hippocampal tissue was collected 120 min after stress onset. Brain-derived neurotrophic factor (BDNF) along with glucocorticoid (GR) and mineralocorticoid (MR) receptors was determined by Western blot analysis. Results indicated injury-dependent changes in glucocorticoid and mineralocorticoid receptors that were influenced by the presence of dexamethasone. Control and FPI rats responded differentially to DEX in that GR increases after receiving the lower dose of DEX were longer lasting in the FPI group. A suppression of MR was found at PID 1 in vehicle-treated FPI and Sham groups. Decreases in the precursor form of BDNF were observed in different FPI groups at PIDs 7 and 14. These findings suggest that the increased sensitivity to stressful events during the first post-injury weeks, after a mild FPI, has an impact on hippocampal neuroplasticity. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. New detection of brain dopamine receptors with [3H]dihydroergocryptine

    International Nuclear Information System (INIS)

    Tittler, M.; Weinreich, P.; Seeman, P.

    1977-01-01

    Because dihydroergocryptine (DHE) and closely related ergots are dopamine-mimetic agonists, we tested [ 3 H]DHE as a possible ligand for [ 3 H]dopamine receptors in the calf caudate. In order to avoid [ 3 H]DHE from tagging α-adrenergic receptors, an excess of 500 nM phentolamine was used to block these sites, permitting the dopamine receptors to be measured separately. Specific binding of [ 3 H]DHE was defined as total binding minus that occurring in the presence of 1 μM (+)-butaclamol. Excess phentolamine reduced the specific binding of [ 3 H]DHE from 328 down to 138 fmol/mg, the difference presumably representing α-receptors. The K/sub D/ for [ 3 H]DHE was 0.55 nM (with or without phentolamine), and this high affinity site was blocked (in the presence of phentolamine) by 250 nM apomorphine, 650 nM dopamine, and 1200 nM (-)-norepinephrine, indicating that [ 3 H]DHE was binding to dopamine receptors. All neuroleptics blocked specific [ 3 H]DHE binding in direct relation to the clinical potency of the neuroleptic. The displacement of specific [ 3 H]DHE binding by dopamine or by norepinephrine (in the presence of phentolamine) revealed two subsets of dopamine receptors

  7. Cyclopentadienyl tricarbonyl complexes of 99mTc for the in vivo imaging of the serotonin 5-HT 1a receptor in the brain

    International Nuclear Information System (INIS)

    Saidi, Mouldi; Trabelsi, Adel; MEKNI, Abdelkader; Kretzschmar, M.; Sefert, S.; Bergmann, R.; Pietzsch, H.-J.

    2005-01-01

    The present interest in the 5-HT 1a receptor is due to its implicated role in several major neuropsychiatric disorders such as depression, eating disorders and anxiety. For the diagnosis of these pathophysiological processes it is important to have radioligands in hand able to specifically bind on the 5-HT 1a receptor in order to allow brain imaging. due to the optimal radiation properties of 99mTc there is a considerable interest in the development of 99mTc radiopharmaceuticals for imaging serotonergic CNS receptors using single-photon emission tomography (SPET). Here we introduce two cyclopentadienyl technitium tricarbonyl conjugates of piperidine derivatives which show high accumulation of radioactivity in brain areas rich in 5-HT 1a receptors

  8. Opioid receptor imaging and displacement studies with [6-O-[{sup 11}C]methyl]buprenorphine in baboon brain

    Energy Technology Data Exchange (ETDEWEB)

    Galynker, Igor; Schlyer, David J.; Dewey, Stephen L.; Fowler, Joanna S.; Logan, Jean; Gatley, S. John; MacGregor, Robert R.; Ferrieri, Richard A.; Holland, M. J.; Brodie, Jonathan; Simon, Eric; Wolf, Alfred P

    1996-04-01

    Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[{sup 11}C]methyl]buprenorphine ([{sup 11}C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% {+-} 2.2% and 43% {+-} 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [{sup 11}C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal (< 15%) effects on cerebellum. Naloxone treatment significantly reduced the slope of the Patlak plot in receptor-containing regions. These results demonstrate that [{sup 11}C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi.

  9. Multicompartmental study of fluorine-18 altanserin binding to brain 5HT2 receptors in humans using positron emission tomography

    International Nuclear Information System (INIS)

    Biver, F.; Goldman, S.; Luxen, A.; Monclus, M.; Forestini, M.; Mendlewicz, J.; Lotstra, F.

    1994-01-01

    Serotoninergic type 2 (5HT 2 ) receptors have been implicated in the regulation of many brain functions in humans and may play a role in several neurological and psychiatric diseases. Fluorine-18 altanserin has been proposed as a new radiotracer for the study of 5HT 2 receptors by PET because of its high affinity for 5HT 2 receptors (Ki: 0.13 nM) and its good specificity in in vitro studies. Dynamic PET studies were carried out in 12 healthy volunteers after intravenous injection of 0.1 mCi/kg [ 18 F] altanserin. Ninety minutes after injection, we observed mainly cortical binding. Basal ganglia and cerebellum showed very low uptake and the frontal cortex to cerebellum ratio was about 3. To evaluate the quantitative distribution of this ligand in the brain, we used two different methods of data analysis: a four-compartment model was used to achieve quantitative evaluation of rate constants (K 1 and k 2 through k 6 ) by non-linear regression, and a multiple-time graphical analysis technique for reversible binding was employed for the measurement of k 1 /k 2 and k 3 /k 4 ratios. Using both methods, we found significant differences in binding capacity (estimated by k 3 /k 4 = B max /K d ) between regions, the values increasing as follows: occipital, limbic, parietal, frontal and temporal cortex. After correction of values obtained by the graphical method for the existence of non-specific binding, results generated by the two methods were consistent. (orig.)

  10. The anabolic steroid nandrolone alters cannabinoid self-administration and brain CB1 receptor density and function.

    Science.gov (United States)

    Struik, Dicky; Fadda, Paola; Zara, Tamara; Zamberletti, Erica; Rubino, Tiziana; Parolaro, Daniela; Fratta, Walter; Fattore, Liana

    2017-01-01

    Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CB 1 receptor agonist WIN55,212-2 (WIN) in rats. Lister Hooded male rats were treated intramuscularly with nandrolone (15mg/kg) or vehicle for 14 consecutive days, and then allowed to self-administer WIN (12.5μg/kg/infusion) intravenously. After reaching stable drug intake, self-administration behavior was extinguished to examine drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Other behavioral parameters presumed to influence drug-taking and drug-seeking behaviors were examined to gain more insight into the behavioral specificity of nandrolone treatment. Finally, animals were sacrificed for analysis of CB 1 receptor density and function in selected brain areas. We found that nandrolone-treated rats self-administered up to 2 times more cannabinoid than vehicle-treated rats, but behaved similarly to control rats when tested for drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Enhanced cannabinoid intake by nandrolone-treated rats was not accompanied by changes in locomotor activity, sensorimotor gating, or memory function. However, our molecular data show that after chronic WIN self-administration nandrolone-treated rats display altered CB 1 receptor density and function in selected brain areas. We hypothesize that increased cannabinoid self-administration in nandrolone-treated rats results from a nandrolone-induced decrease in reward function, which rats seem to compensate by voluntarily increasing their cannabinoid intake. Altogether, our findings corroborate the hypothesis that chronic exposure to anabolic-androgenic steroids induces dysfunction of the reward pathway in rats and might represent a potential risk factor for abuse of

  11. Regional differences in mu and kappa opioid receptor G-protein activation in brain in male and female prairie voles.

    Science.gov (United States)

    Martin, T J; Sexton, T; Kim, S A; Severino, A L; Peters, C M; Young, L J; Childers, S R

    2015-12-17

    Prairie voles are unusual mammals in that, like humans, they are capable of forming socially monogamous pair bonds, display biparental care, and engage in alloparental behaviors. Both mu and kappa opioid receptors are involved in behaviors that either establish and maintain, or result from pair bond formation in these animals. Mu and kappa opioid receptors both utilize inhibitory G-proteins in signal transduction mechanisms, however the efficacy by which these receptor subtypes stimulate G-protein signaling across the prairie vole neuraxis is not known. Utilizing [(35)S]GTPγS autoradiography, we characterized the efficacy of G-protein stimulation in coronal sections throughout male and female prairie vole brains by [D-Ala2,NMe-Phe4,Gly-ol5]-enkephalin (DAMGO) and U50,488H, selective mu and kappa opioid agonists, respectively. DAMGO stimulation was highest in the forebrain, similar to that found with other rodent species. U-50,488H produced greater stimulation in prairie voles than is typically seen in mice and rats, particularly in select forebrain areas. DAMGO produced higher stimulation in the core versus the shell of the nucleus accumbens (NAc) in females, while the distribution of U-50,488H stimulation was the opposite. There were no gender differences for U50,488H stimulation of G-protein activity across the regions examined, while DAMGO stimulation was greater in sections from females compared to those from males for NAc core, entopeduncular nucleus, and hippocampus. These data suggest that the kappa opioid system may be more sensitive to manipulation in prairie voles compared to mice and rats, and that female prairie voles may be more sensitive to mu agonists in select brain regions than males. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Quantification of GABAA receptors in the rat brain with [123I]Iomazenil SPECT from factor analysis-denoised images

    International Nuclear Information System (INIS)

    Tsartsalis, Stergios; Moulin-Sallanon, Marcelle; Dumas, Noé; Tournier, Benjamin B.; Ghezzi, Catherine; Charnay, Yves; Ginovart, Nathalie; Millet, Philippe

    2014-01-01

    Purpose: In vivo imaging of GABA A receptors is essential for the comprehension of psychiatric disorders in which the GABAergic system is implicated. Small animal SPECT provides a modality for in vivo imaging of the GABAergic system in rodents using [ 123 I]Iomazenil, an antagonist of the GABA A receptor. The goal of this work is to describe and evaluate different quantitative reference tissue methods that enable reliable binding potential (BP) estimations in the rat brain to be obtained. Methods: Five male Sprague–Dawley rats were used for [ 123 I]Iomazenil brain SPECT scans. Binding parameters were obtained with a one-tissue compartment model (1TC), a constrained two-tissue compartment model (2TC c ), the two-step Simplified Reference Tissue Model (SRTM2), Logan graphical analysis and analysis of delayed-activity images. In addition, we employed factor analysis (FA) to deal with noise in data. Results: BP ND obtained with SRTM2, Logan graphical analysis and delayed-activity analysis was highly correlated with BP F values obtained with 2TC c (r = 0.954 and 0.945 respectively, p c and SRTM2 in raw and FA-denoised images (r = 0.961 and 0.909 respectively, p ND values from raw images while scans of only 70 min are sufficient from FA-denoised images. These images are also associated with significantly lower standard errors of 2TC c and SRTM2 BP values. Conclusion: Reference tissue methods such as SRTM2 and Logan graphical analysis can provide equally reliable BP ND values from rat brain [ 123 I]Iomazenil SPECT. Acquisitions, however, can be much less time-consuming either with analysis of delayed activity obtained from a 20-minute scan 50 min after tracer injection or with FA-denoising of images

  13. Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

    OpenAIRE

    Andreas Stengel; Yvette F. Taché; Yvette F. Taché

    2017-01-01

    Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a br...

  14. Kinetic analysis of the cannabinoid-1 receptor PET tracer [{sup 18}F]MK-9470 in human brain

    Energy Technology Data Exchange (ETDEWEB)

    Sanabria-Bohorquez, Sandra Marina; Hamill, Terence G.; Burns, H.D. [Merck Research Laboratories, Imaging, West Point, PA (United States); Goffin, Karolien; Laere, Koen van [University Hospital and K.U. Leuven, Division of Nuclear Medicine, Leuven (Belgium); Lepeleire, Inge de [Merck Research Laboratories, Brussels (Belgium); Bormans, Guy [K.U. Leuven, Laboratory of Radiopharmacy, Leuven (Belgium)

    2010-05-15

    Quantitative imaging of the type 1 cannabinoid receptor (CB1R) opens perspectives for many neurological and psychiatric disorders. We characterized the kinetics and reproducibility of the CB1R tracer [{sup 18}F]MK-9470 in human brain. [{sup 18}F]MK-9470 data were analysed using reversible models and the distribution volume V{sub T} and V{sub ND} k{sub 3} (V{sub ND} k{sub 3} = K{sub 1} k{sub 2}) were estimated. Tracer binding was also evaluated using irreversible kinetics and the irreversible uptake constant K{sub i} and fractional uptake rate (FUR) were estimated. The effect of blood flow on these parameters was evaluated. Additionally, the possibility of determining the tracer plasma kinetics using a reduced number of blood samples was also examined. A reversible two-tissue compartment model using a global k{sub 4} value was necessary to describe brain kinetics. Both V{sub T} and V{sub ND} k{sub 3} were estimated satisfactorily and their test-retest variability was between 10% and 30%. Irreversible methods adequately described brain kinetics and FUR values were equivalent to K{sub i}. The linear relationship between K{sub i} and V{sub ND} k{sub 3} demonstrated that K{sub i} or FUR and thus the simple measure of tracer brain uptake provide CB1R availability information. The test-retest variability of K{sub i} and FUR was <10% and estimates were independent of blood flow. Brain uptake can be used as a receptor availability index, albeit at the expense of potential bias due to between-subject differences in tracer plasma kinetics. [{sup 18}F]MK-9470 specific binding can be accurately determined using FUR values requiring a short scan 90 to 120 min after tracer administration. Our results suggest that [{sup 18}F]MK-9470 plasma kinetics can be assessed using a few venous samples. (orig.)

  15. Adult naked mole-rat brain retains the NMDA receptor subunit GluN2D associated with hypoxia tolerance in neonatal mammals.

    Science.gov (United States)

    Peterson, Bethany L; Park, Thomas J; Larson, John

    2012-01-11

    Adult naked mole-rats show a number of systemic adaptations to a crowded underground habitat that is low in oxygen and high in carbon dioxide. Remarkably, brain slice tissue from adult naked mole-rats also is extremely tolerant to oxygen deprivation as indicated by maintenance of synaptic transmission under hypoxic conditions as well as by a delayed neuronal depolarization during anoxia. These characteristics resemble hypoxia tolerance in brain slices from neonates in a variety of mammal species. An important component of neonatal tolerance to hypoxia involves the subunit composition of NMDA receptors. Neonates have a high proportion of NMDA receptors with GluN2D subunits which are protective because they retard calcium entry into neurons during hypoxic episodes. Therefore, we hypothesized that adult naked mole-rats retain a protective, neonatal-like, NMDA receptor subunit profile. We used immunoblotting to assess age-related changes in NMDA receptor subunits in naked mole-rats and mice. The results show that adult naked mole-rat brain retains a much greater proportion of the hypoxia-protective GluN2D subunit compared to adult mice. However, age-related changes in other subunits (GluN2A and GluN2B) from the neonatal period to adulthood were comparable in mice and naked mole-rats. Hence, adult naked mole-rat brain only retains the neonatal NMDA receptor subunit that is associated with hypoxia tolerance. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  16. Preclinical evaluation and quantification of [(18)F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain

    OpenAIRE

    Casteels, Cindy; Koole, Michel; Celen, Sofie; Bormans, Guy; Van Laere, Koen

    2012-01-01

    PURPOSE: [(18)F]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [(18)F]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain. METHODS: Dynamic small-animal PET scans with [(18)F]MK-9470 were performed in Wistar rats on a FOCUS-220 system for up to 10 h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Displacement and blo...

  17. Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin.

    Science.gov (United States)

    Bernasconi, Fosco; Schmidt, André; Pokorny, Thomas; Kometer, Michael; Seifritz, Erich; Vollenweider, Franz X

    2014-12-01

    Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood. Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration. Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168-189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211-242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168-189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211-242 ms interval. Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down control. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2.

    Science.gov (United States)

    Tang, Jun; Chen, Qianwei; Guo, Jing; Yang, Liming; Tao, Yihao; Li, Lin; Miao, Hongping; Feng, Hua; Chen, Zhi; Zhu, Gang

    2016-04-01

    Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns leading to detrimental neurological sequelae. Minocycline has been reported to play a key role in neurological inflammatory diseases by controlling some mechanisms that involve cannabinoid receptor 2 (CB2R). The current study investigated whether minocycline reduces neuroinflammation and protects the brain from injury in a rat model of collagenase-induced GMH by regulating CB2R activity. To test this hypothesis, the effects of minocycline and a CB2R antagonist (AM630) were evaluated in male rat pups that were post-natal day 7 (P7) after GMH. We found that minocycline can lead to increased CB2R mRNA expression and protein expression in microglia. Minocycline significantly reduced GMH-induced brain edema, microglial activation, and lateral ventricular volume. Additionally, minocycline enhanced cortical thickness after injury. All of these neuroprotective effects of minocycline were prevented by AM630. A cannabinoid CB2 agonist (JWH133) was used to strengthen the hypothesis, which showed the identical neuroprotective effects of minocycline. Our study demonstrates, for the first time, that minocycline attenuates neuroinflammation and brain injury in a rat model of GMH, and activation of CBR2 was partially involved in these processes.

  19. Development of receptors for insulin and insulin-like growth factor-I in head and brain of chick embryos: Autoradiographic localization

    International Nuclear Information System (INIS)

    Bassas, L.; Girbau, M.; Lesniak, M.A.; Roth, J.; de Pablo, F.

    1989-01-01

    In whole brain of chick embryos insulin receptors are highest at the end of embryonic development, while insulin-like growth factor-I (IGF-I) receptors dominate in the early stages. These studies provided evidence for developmental regulation of both types of receptors, but they did not provide information on possible differences between brain regions at each developmental stage or within one region at different embryonic ages. We have now localized the specific binding of [125I]insulin and [125I]IGF-I in sections of head and brain using autoradiography and computer-assisted densitometric analysis. Embryos have been studied from the latter part of organogenesis (days 6 and 12) through late development (day 18, i.e. 3 days before hatching), and the binding patterns have been compared with those in the adult brain. At all ages the binding of both ligands was to discrete anatomical regions. Interestingly, while in late embryos and adult brain the patterns of [125I]insulin and [125I] IGF-I binding were quite distinct, in young embryos both ligands showed very similar localization of binding. In young embryos the retina and lateral wall of the growing encephalic vesicles had the highest binding of both [125I]insulin and [125I]IGF-I. In older embryos, as in the adult brain, insulin binding was high in the paleostriatum augmentatum and molecular layer of the cerebellum, while IGF-I binding was prominent in the hippocampus and neostriatum. The mapping of receptors in a vertebrate embryo model from early prenatal development until adulthood predicts great overlap in any possible function of insulin and IGF-I in brain development, while it anticipates differential localized actions of the peptides in the mature brain

  20. In vivo binding of 125I-LSD to serotonin 5-HT2 receptors in mouse brain

    International Nuclear Information System (INIS)

    Hartig, P.R.; Scheffel, U.; Frost, J.J.; Wagner, H.N. Jr.

    1985-01-01

    The binding of 125 I-LSD (2-[ 125 I]-lysergic acid diethylamide) was studied in various mouse brain regions following intravenous injection of the radioligand. The high specific activity of 125 I-LSD enabled the injection of low mass doses (14ng/kg), which are well below the threshold for induction of any known physiological effect of the probe. The highest levels of 125 I-LSD binding were found in the frontal cortex, olfactory tubercles, extra-frontal cortex and striatum while the lowest level was found in the cerebellum. Binding was saturable in the frontal cortex but increased linearly in the cerebellum with increasing doses of 125 I-LSD. Serotonergic compounds potently inhibited 125 I-LSD binding in cortical regions, olfactory tubercles, and hypothalamus but had no effect in the cerebellum. Dopaminergic compounds caused partial inhibition of binding in the striatum while adrenergic compounds were inactive. From these studies the authors conclude that 125 I-LSD labels serotonin 5-HT 2 receptor sites in cortical regions with no indication that other receptor sites are labeled. In the olfactory tubercles and hypothalamus, 125 I-LSD labeling occurs predominantly or entirely at serotonic 5-HT 2 sites. In the striatum, 125 I-LSD labels approximately equal proportions of serotonergic and dopaminergic sites. These data indicate that 125 I-LSD labels serotonin receptors in vivo and suggests that appropriate derivatives of 2I-LSD may prove useful for tomographic imaging of serotonin 5-HT 2 receptors in the mammalian cortex

  1. Thyrotropin-releasing hormone (TRH) receptors. Localization by light microscopic autoradiography in rat brain using [3H][3-Me-His2]TRH as the radioligand

    International Nuclear Information System (INIS)

    Mantyh, P.W.; Hunt, S.P.

    1985-01-01

    Thyrotropin releasing hormone (TRH) is a putative neurotransmitter in both the central and peripheral nervous system. In the present report, we have used autoradiography coupled with densitometric analysis of tritium-sensitive film to investigate the distribution of [ 3 H][3-Me-His2]TRH [( 3 H]MeTRH)-binding sizes in the rat brain. Previous pharmacological reports have established that many of these [ 3 H]MeTRH-binding sites have a structure-activity profile consistent with being a physiological TRH receptor. A high level of TRH receptors were observed in the accessory olfactory bulb, lateral nucleus of the amygdala, dentate gyrus, and entorhinal cortex. Moderate levels of TRH receptors were observed in the rhinal cortex, hypothalamus, superior colliculus, several brainstem motor nuclei, and lamina I of the spinal trigeminal nucleus pars candalis, while low concentrations of receptors are present in the cerebral cortex, striatum and ventral horn of the spinal cord. Very low levels of receptors were observed in the globus pallidus and in most nuclei of the dorsal thalamus. Comparisons of the distribution of TRH receptors to TRH-immunoreactive content indicates that, while in some areas of the brain there is a rough correlation between levels of TRH peptide and its receptor, in most brain areas there is little obvious correlation between the two. While such a discrepancy has been observed for other peptides and their receptors, the extensive distribution of TRH receptors in the central nervous system does provide an explanation for the variety of behavioral effects observed when TRH is infused into the central nervous system

  2. Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury

    DEFF Research Database (Denmark)

    Jansen, Pernille; Giehl, Klaus; Nyengaard, Jens R

    2007-01-01

    Neurotrophins are essential for development and maintenance of the vertebrate nervous system. Paradoxically, although mature neurotrophins promote neuronal survival by binding to tropomyosin receptor kinases and p75 neurotrophin receptor (p75(NTR)), pro-neurotrophins induce apoptosis in cultured......)/sortilin receptor complex to neuronal viability. In the developing retina, Sortilin 1 (Sort1)(-/-) mice showed reduced neuronal apoptosis that was indistinguishable from that observed in p75(NTR)-deficient (Ngfr(-/-)) mice. To our surprise, although sortilin deficiency did not affect developmentally regulated...... apoptosis of sympathetic neurons, it did prevent their age-dependent degeneration. Furthermore, in an injury protocol, lesioned corticospinal neurons in Sort1(-/-) mice were protected from death. Thus, the sortilin pathway has distinct roles in pro-neurotrophin-induced apoptotic signaling in pathological...

  3. Brain serotonin 2A receptor binding: Relations to body mass index, tobacco and alcohol use

    DEFF Research Database (Denmark)

    Erritzoe, D.; Frokjaer, V. G.; Haugbol, S.

    2009-01-01

    receptor (5-HT(2A)) in humans, we tested in 136 healthy human subjects if body mass index (BMI), degree of alcohol consumption and tobacco smoking was associated to the cerebral in vivo 5-HT(2A) receptor binding as measured with (18)F-altanserin PET. The subjects' BMI's ranged from 18.4 to 42.8 (25.......2+/-4.3) kg/m(2). Cerebral cortex 5-HT(2A) binding was significantly positively correlated to BMI, whereas no association between cortical 5-HT(2A) receptor binding and alcohol or tobacco use was detected. We suggest that our observation is driven by a lower central 5-HT level in overweight people, leading...

  4. Special issues in quantitation of brain receptors and related markers by emission computed tomography

    International Nuclear Information System (INIS)

    Links, J.M.

    1998-01-01

    Emission computed tomography provides an opportunity to quantify neurotransmitter-neuro receptor systems in vivo. In order to do so, very high image quality and quantitative accuracy are required. Quantitation of receptor systems involves considerations of physical effects (such as finite spatial resolution, scatter, and attenuation), instrumentation design (such as spatial sampling), image processing (such as filtering), and data analysis (such as kinetic modeling). Appropriate application of these considerations can lead to useful results, but emerging approaches promise even greater levels of accuracy and precision

  5. Application of 5-hydroxytryptamine receptor imaging for study of neuropsychiatric disorders and brain functions

    International Nuclear Information System (INIS)

    Qiu Chun; Guan Yihui

    2011-01-01

    In the central nervous system, the widely distributed 5-hydroxytryptamine (5-HT)receptors are involved in regulating a large number of psychological and physiological functions, including mood, sleep, endocrine and autonomic nervous system. Abnormal 5-HT transmission has been implicated in a variety of neuropsychiatric disorders, such as pain, depression and epilepsy. With the development of radioligands, non-invasive nuclear imaging technique with exquisite sensitivity and specificity has been applied for delineation of neurotransmitter function in vivo. It does great benefit for researches of these diseases and development of drugs. This review provided an overview of 5-HT receptors radioligands and recent findings. (authors)

  6. Validation of antibodies for neuroanatomical localization of the P2Y receptor in macaque brain

    DEFF Research Database (Denmark)

    Dreisig, Karin; Degn, Matilda; Sund, Louise

    2016-01-01

    Focus on the purinergic receptor P2Y11 has increased following the finding of an association between the sleep disorder narcolepsy and a genetic variant in P2RY11 causing decreased gene expression. Narcolepsy is believed to arise from an autoimmune destruction of the hypothalamic neurons that pro......Focus on the purinergic receptor P2Y11 has increased following the finding of an association between the sleep disorder narcolepsy and a genetic variant in P2RY11 causing decreased gene expression. Narcolepsy is believed to arise from an autoimmune destruction of the hypothalamic neurons...

  7. Synthesis and evaluation of [125I]I-TSA as a brain nicotinic acetylcholine receptor α7 subtype imaging agent

    International Nuclear Information System (INIS)

    Ogawa, Mikako; Tatsumi, Ryo; Fujio, Masakazu; Katayama, Jiro; Magata, Yasuhiro

    2006-01-01

    Introduction: Some in vitro investigations have suggested that the nicotinic acetylcholine receptor (nAChR) α 7 subtype is implicated in Alzheimer's disease, schizophrenia and others. Recently, we developed (R)-3'-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'-[1',3'] oxazolidin]-2'-one (Br-TSA), which has a high affinity and selectivity for α 7 nAChRs. Therefore we synthesized (R)-3'-(5-[ 125 I]iodothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'- [1',3']oxazolidin]-2'-one ([ 125 I]I-TSA) and evaluated its potential for the in vivo detection of α 7 nAChR in brain. Methods: In vitro binding affinity of I-TSA was measured in rat brain homogenates. Radioiodination was accomplished by a Br-I exchange reaction. Biodistribution studies were undertaken in mice by tail vein injection of [ 125 I]I-TSA. In vivo receptor blocking studies were carried out by treating mice with methyllycaconitine (MLA; 5 nmol/5 μl, i.c.v.) or nonradioactive I-TSA (50 μmol/kg, i.v.). Results: I-TSA exhibited a high affinity and selectivity for the α 7 nAChR (K i for α 7 nAChR=0.54 nM). Initial uptake in the brain was high (4.42 %dose/g at 5 min), and the clearance of radioactivity was relatively slow in the hippocampus (α 7 nAChR-rich region) and was rather rapid in the cerebellum (α 7 nAChR poor region). The hippocampus to cerebellum uptake ratio was 0.9 at 5 min postinjection, but it was increased to 1.8 at 60 min postinjection. Although the effect was not statistically significant, administration of I-TSA and MLA decreased the accumulation of radioactivity in hippocampus. Conclusion: Despite its high affinity and selectivity, [ 125 I]I-TSA does not appear to be a suitable tracer for in vivo α 7 nAChR receptor imaging studies due to its high nonspecific binding. Further structural optimization is needed

  8. Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease.

    Science.gov (United States)

    Köfalvi, Attila; Lemos, Cristina; Martín-Moreno, Ana M; Pinheiro, Bárbara S; García-García, Luis; Pozo, Miguel A; Valério-Fernandes, Ângela; Beleza, Rui O; Agostinho, Paula; Rodrigues, Ricardo J; Pasquaré, Susana J; Cunha, Rodrigo A; de Ceballos, María L

    2016-11-01

    Cannabinoid CB2 receptors (CB2Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB2Rs in the regulation of glucose uptake in the mouse brain. To that aim, we have undertaken 1) measurement of (3)H-deoxyglucose uptake in cultured cortical astrocytes and neurons and in acute hippocampal slices; 2) real-time visualization of fluorescently labeled deoxyglucose uptake in superfused hippocampal slices; and 3) in vivo PET imaging of cerebral (18)F-fluorodeoxyglucose uptake. We now show that both selective (JWH133 and GP1a) as well as non-selective (WIN55212-2) CB2R agonists, but not the CB1R-selective agonist, ACEA, stimulate glucose uptake, in a manner that is sensitive to the CB2R-selective antagonist, AM630. Glucose uptake is stimulated in astrocytes and neurons in culture, in acute hippocampal slices, in different brain areas of young adult male C57Bl/6j and CD-1 mice, as well as in middle-aged C57Bl/6j mice. Among the endocannabinoid metabolizing enzymes, the selective inhibition of COX-2, rather than that of FAAH, MAGL or α,βDH6/12, also stimulates the uptake of glucose in hippocampal slices of middle-aged mice, an effect that was again prevented by AM630. However, we found the levels of the endocannabinoid, anandamide reduced in the hippocampus of TgAPP-2576 mice (a model of β-amyloidosis), and likely as a consequence, COX-2 inhibition failed to stimulate glucose uptake in these mice. Together, these results reveal a novel general glucoregulatory role for CB2Rs in the brain, raising therapeutic interest in CB2R agonists as nootropic agents. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Oxytocin receptor polymorphism and childhood social experiences shape adult personality, brain structure and neural correlates of mentalizing.

    Science.gov (United States)

    Schneider-Hassloff, H; Straube, B; Jansen, A; Nuscheler, B; Wemken, G; Witt, S H; Rietschel, M; Kircher, T

    2016-07-01

    The oxytocin system is involved in human social behavior and social cognition such as attachment, emotion recognition and mentalizing (i.e. the ability to represent mental states of oneself and others). It is shaped by social experiences in early life, especially by parent-infant interactions. The single nucleotid polymorphism rs53576 in the oxytocin receptor (OXTR) gene has been linked to social behavioral phenotypes. In 195 adult healthy subjects we investigated the interaction of OXTR rs53576 and childhood attachment security (CAS) on the personality traits "adult attachment style" and "alexithymia" (i.e. emotional self-awareness), on brain structure (voxel-based morphometry) and neural activation (fMRI) during an interactive mentalizing paradigm (prisoner's dilemma game; subgroup: n=163). We found that in GG-homozygotes, but not in A-allele carriers, insecure childhood attachment is - in adulthood - associated with a) higher attachment-related anxiety and alexithymia, b) higher brain gray matter volume of left amygdala and lower volumes in right superior parietal lobule (SPL), left temporal pole (TP), and bilateral frontal regions, and c) higher mentalizing-related neural activity in bilateral TP and precunei, and right middle and superior frontal gyri. Interaction effects of genotype and CAS on brain volume and/or function were associated with individual differences in alexithymia and attachment-related anxiety. Interactive effects were in part sexually dimorphic. The interaction of OXTR genotype and CAS modulates adult personality as well as brain structure and function of areas implicated in salience processing and mentalizing. Rs53576 GG-homozygotes are partially more susceptible to childhood attachment experiences than A-allele carriers. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Social status and sex independently influence androgen receptor expression in the eusocial naked mole-rat brain.

    Science.gov (United States)

    Holmes, Melissa M; Goldman, Bruce D; Forger, Nancy G

    2008-08-01

    Naked mole-rats (Heterocephalus glaber) are eusocial rodents that live in large subterranean colonies including a single breeding female and 1-3 breeding males; all other members of the colony, known as subordinates, are reproductively suppressed. We recently found that naked mole-rats lack many of the sex differences in the brain and spinal cord commonly found in other rodents. Instead, neural morphology is influenced by breeding status, such that breeders, regardless of sex, have more neurons than subordinates in the ventromedial nucleus of the hypothalamus (VMH), and larger overall volumes of the bed nucleus of the stria terminalis (BST), paraventricular nucleus (PVN) and medial amygdala (MeA). To begin to understand how breeding status influences brain morphology, we examined the distribution of androgen receptor (AR) immunoreactivity in gonadally intact breeders and subordinates of both sexes. All animals had AR+ nuclei in many of the same regions positive for AR in other mammals, including the VMH, BST, PVN, MeA, and the ventral portion of the premammillary nucleus (PMv). We also observed diffuse labeling throughout the preoptic area, demonstrating that distribution of the AR protein in presumptive reproductive brain nuclei is well-conserved, even in a species that exhibits remarkably little sexual dimorphism. In contrast to other rodents, however, naked mole-rats lacked AR+ nuclei in the suprachiasmatic nucleus and hippocampus. Males had more AR+ nuclei in the MeA, VMH, and PMv than did females. Surprisingly, breeders had significantly fewer AR+ nuclei than subordinates in all brain regions examined (VMH, BST, PVN, MeA, and PMv). Thus, social status is strongly correlated with AR immunoreactivity in this eusocial species.

  11. Kinetic analysis of the cannabinoid-1 receptor PET tracer [18F]MK-9470 in human brain

    International Nuclear Information System (INIS)

    Sanabria-Bohorquez, Sandra Marina; Hamill, Terence G.; Burns, H.D.; Goffin, Karolien; Laere, Koen van; Lepeleire, Inge de; Bormans, Guy

    2010-01-01

    Quantitative imaging of the type 1 cannabinoid receptor (CB1R) opens perspectives for many neurological and psychiatric disorders. We characterized the kinetics and reproducibility of the CB1R tracer [ 18 F]MK-9470 in human brain. [ 18 F]MK-9470 data were analysed using reversible models and the distribution volume V T and V ND k 3 (V ND k 3 = K 1 k 2 ) were estimated. Tracer binding was also evaluated using irreversible kinetics and the irreversible uptake constant K i and fractional uptake rate (FUR) were estimated. The effect of blood flow on these parameters was evaluated. Additionally, the possibility of determining the tracer plasma kinetics using a reduced number of blood samples was also examined. A reversible two-tissue compartment model using a global k 4 value was necessary to describe brain kinetics. Both V T and V ND k 3 were estimated satisfactorily and their test-retest variability was between 10% and 30%. Irreversible methods adequately described brain kinetics and FUR values were equivalent to K i . The linear relationship between K i and V ND k 3 demonstrated that K i or FUR and thus the simple measure of tracer brain uptake provide CB1R availability information. The test-retest variability of K i and FUR was 18 F]MK-9470 specific binding can be accurately determined using FUR values requiring a short scan 90 to 120 min after tracer administration. Our results suggest that [ 18 F]MK-9470 plasma kinetics can be assessed using a few venous samples. (orig.)

  12. Biological sex influences learning strategy preference and muscarinic receptor binding in specific brain regions of prepubertal rats.

    Science.gov (United States)

    Grissom, Elin M; Hawley, Wayne R; Hodges, Kelly S; Fawcett-Patel, Jessica M; Dohanich, Gary P

    2013-04-01

    According to the theory of multiple memory systems, specific brain regions interact to determine how the locations of goals are learned when rodents navigate a spatial environment. A number of factors influence the type of strategy used by rodents to remember the location of a given goal in space, including the biological sex of the learner. We recently found that prior to puberty male rats preferred a striatum-dependent stimulus-response strategy over a hippocampus-dependent place strategy when solving a dual-solution task, while age-matched females showed no strategy preference. Because the cholinergic system has been implicated in learning strategy and is known to be sexually dimorphic prior to puberty, we explored the relationship between learning strategy and muscarinic receptor binding in specific brain regions of prepubertal males and female rats. We confirmed our previous finding that at 28 days of age a significantly higher proportion of prepubertal males preferred a stimulus-response learning strategy than a place strategy to solve a dual-solution visible platform water maze task. Equal proportions of prepubertal females preferred stimulus-response or place strategies. Profiles of muscarinic receptor binding as assessed by autoradiography varied according to strategy preference. Regardless of biological sex, prepubertal rats that preferred stimulus-response strategy exhibited lower ratios of muscarinic receptor binding in the hippocampus relative to the dorsolateral striatum compared to rats that preferred place strategy. Importantly, much of the variance in this ratio was related to differences in the ventral hippocampus to a greater extent than the dorsal hippocampus. The ratios of muscarinic receptors in the hippocampus relative to the basolateral amygdala also were lower in rats that preferred stimulus-response strategy over place strategy. Results confirm that learning strategy preference varies with biological sex in prepubertal rats with males

  13. Exercise preconditioning reduces brain damage and inhibits TNF-alpha receptor expression after hypoxia/reoxygenation: an in vivo and in vitro study.

    Science.gov (United States)

    Ding, Yun-Hong; Mrizek, Michael; Lai, Qin; Wu, Yimin; Reyes, Raul; Li, Jie; Davis, William W; Ding, Yuchuan

    2006-11-01

    Exercise reduces ischemia and reperfusion injury in rat stroke models. We investigated whether gradual increases in tumor necrosis factor-alpha (TNF-alpha) reported during exercise down-regulates expression of TNF-alpha receptors I and II (TNFRI and II) in stroke, leading to reduced brain damage. Adult male Sprague Dawley rats were subjected to 30 minutes of exercise on a treadmill each day for 3 weeks. Then, stroke was induced by a 2-hour middle cerebral artery (MCA) occlusion using an intra-luminal filament. Expressions of TNFRI and II mRNA in the brain were detected using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Protein expressions of TNFRI and II were determined by enzyme-linked immunoabsorbant assay (ELISA) in serum and brain homogenates. Spatial distribution of TNF-alpha receptors in brain regions was determined with immunocytochemistry. In human umbilical vein endothelial cells (HUVEC), we addressed the causal effect of TNF-alpha pretreatment on TNF I and II expression using ELISA and real-time PCR. In exercised rats after stroke, brain infarct was significantly (p<0.01) reduced in the entire MCA supplied regions, associated with a mild expression of TNFRI and II mRNA and protein. The TNF-alpha receptors were restricted to the ischemic core. In contrast, a robust expression of TNFRI and II molecules was found in non-exercised rats subjected to similar ischemia/reperfusion insults. An in vitro study revealed a causal link between TNF-alpha pretreatment and reduced cellular expression of TNF-alpha receptors under hypoxic/reoxygenated conditions. Our results suggest that reduced-brain damage in ischemic rats after exercise preconditioning may be attributable to the reduced expression of TNF-alpha receptors. Chronically increased TNF-alpha expression was also found to reduce TNFI and II responding to acute ischemia/reperfusion insult.

  14. Brain penetration of telmisartan, a unique centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques

    International Nuclear Information System (INIS)

    Noda, Akihiro; Fushiki, Hiroshi; Murakami, Yoshihiro; Sasaki, Hiroshi; Miyoshi, Sosuke; Kakuta, Hirotoshi; Nishimura, Shintaro

    2012-01-01

    Introduction: Telmisartan is a widely used, long-acting antihypertensive agent. Known to be a selective angiotensin II type 1 (AT 1 ) receptor (AT 1 R) blocker (ARB), telmisartan acts as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and inhibits centrally mediated effects of angiotensin II in rats following peripheral administration, although the brain penetration of telmisartan remains unclear. We investigated the brain concentration and localization of telmisartan using 11 C-labeled telmisartan and positron emission tomography (PET) in conscious rhesus macaques. Methods: Three male rhesus macaques were bolus intravenously administered [ 11 C]telmisartan either alone or as a mixture with unlabeled telmisartan (1 mg/kg). Dynamic PET images were acquired for 95 min following administration. Blood samples were collected for the analysis of plasma concentration and metabolites, and brain and plasma concentrations were calculated from detected radioactivity using the specific activity of the administered drug preparation, in which whole blood radioactivity was used for the correction of intravascular blood radioactivity in brain. Results: Telmisartan penetrated into the brain little but enough to block AT 1 R and showed a consistently increasing brain/plasma ratio within the PET scanning period, suggesting slow clearance of the compound from the brain compared to the plasma clearance. Brain/plasma ratios at 30, 60, and 90 min were 0.06, 0.13, and 0.18, respectively. No marked localization according to the AT 1 R distribution was noted over the entire brain, even on tracer alone dosing. Conclusions: Telmisartan penetrated into the brain enough to block AT 1 R and showed a slow clearance from the brain in conscious rhesus macaques, supporting the long-acting and central responses of telmisartan as a unique property among ARBs.

  15. Variations in estrogen receptor ? gene and risk of dementia, and brain volumes on MRI.

    NARCIS (Netherlands)

    S.C.E. Schuit (Stephanie); A. Hofman (Albert); P.J. Koudstaal (Peter Jan); C.M. van Duijn (Cornelia); A.G. Uitterlinden (André); H.A.P. Pols (Huib); M.M.B. Breteler (Monique); J.B.J. van Meurs (Joyce); T. den Heijer (Tom)

    2004-01-01

    textabstractThe role of estrogens in Alzheimer's disease (AD) is controversial. We investigated the association between well-recognized, and potentially functional, polymorphisms in the estrogen receptor (ER) gene and the risk of AD in a prospective study of 6056 Caucasian older men and women aged

  16. Excitatory amino acid neurotoxicity and modulation of glutamate receptor expression in organotypic brain slice cultures

    DEFF Research Database (Denmark)

    Zimmer, J; Kristensen, Bjarne Winther; Jakobsen, B

    2000-01-01

    Using organotypic slice cultures of hippocampus and cortex-striatum from newborn to 7 day old rats, we are currently studying the excitotoxic effects of kainic acid (KA), AMPA and NMDA and the neuroprotective effects of glutamate receptor blockers, like NBQX. For detection and quantitation...

  17. Flavylium salts as in vitro precursors of potent ligands to brain GABA-A receptors

    DEFF Research Database (Denmark)

    Kueny-Stotz, Marie; Chassaing, Stefan; Brouillard, Raymond

    2008-01-01

    The synthesis of a series of derivatized flavylium cations was undertaken and the affinity to the benzodiazepine binding site of the GABA-A receptor evaluated. The observed high affinity for some derivatives (sub-muM range) was explained by an in vitro transformation of the flavylium cations into...

  18. A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype

    International Nuclear Information System (INIS)

    Gitler, M.S.; Cohen, V.I.; De La Cruz, R.; Boulay, S.F.; Jin, B.; Zeeberg, B.R.; Reba, R.C.

    1993-01-01

    Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. In our efforts to prepare such a radioligand, the authors have used competition studies against currently existing muscarinic receptor radioligands to infer the in vitro and in vivo properties of a novel muscarinic receptor ligand, 5-[[4-[4-(diisobutylamino)butyl]-1-phenyl]acetyl]-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one (DIBD). In vitro competition studies against [ 3 H](R)-3-quinuclidinylbenzilate ([ 3 H]QNB) and [ 3 H]N-methylscopolamine ([ 3 H]NMS), using membranes derived from transfected cells expressing only m1, m2, m3, or m4 receptor subtypes, indicate that DIBD is selective for m2/m4 over m1/m3. In vivo competition studies against (R,R)-[ 125 I]IQNB indicate that DIBD crosses the blood brain barrier (BBB). The relationship of the regional percentage decrease in (R,R)-[ 125 I]IQNB versus the percentage of each of the receptor subtypes indicates that DIBD competes more effectively in those brain regions which are known to be enriched in the m2, relative to the m1, m3, and m4, receptor subtype; however, analysis of the data using a mathematical model shows that caution is required when interpreting the in vivo results. The authors conclude that a suitably radiolabeled derivative of DIBD may be of potential use in emission tomographic study of changes in m2 receptors in the central nervous system

  19. The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant in patients with traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Rätsep Indrek

    2009-12-01

    Full Text Available Abstract Background Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor. Methods Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE, mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS, the Disability Rating Scale (DRS and a modified version of the Oxford Handicap Scale (HIREOS. Results 228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163 in the combined Anatibant treated group, compared to 19.3% (11/57 in the placebo group (relative risk = 1.37; 95% CI 0·76 to 2·46. All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36. The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures. Conclusion This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in

  20. The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury.

    Science.gov (United States)

    Shakur, Haleema; Andrews, Peter; Asser, Toomas; Balica, Laura; Boeriu, Cristian; Quintero, Juan Diego Ciro; Dewan, Yashbir; Druwé, Patrick; Fletcher, Olivia; Frost, Chris; Hartzenberg, Bennie; Mantilla, Jorge Mejia; Murillo-Cabezas, Francisco; Pachl, Jan; Ravi, Ramalingam R; Rätsep, Indrek; Sampaio, Cristina; Singh, Manmohan; Svoboda, Petr; Roberts, Ian

    2009-12-03

    Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor. Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE), mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS), the Disability Rating Scale (DRS) and a modified version of the Oxford Handicap Scale (HIREOS). 228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163) in the combined Anatibant treated group, compared to 19.3% (11/57) in the placebo group (relative risk = 1.37; 95% CI 0.76 to 2.46). All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36). The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures. This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in the risk of serious adverse events was reduced. This trial

  1. Harmaline competitively inhibits [3H]MK-801 binding to the NMDA receptor in rabbit brain.

    Science.gov (United States)

    Du, W; Aloyo, V J; Harvey, J A

    1997-10-03

    Harmaline, a beta-carboline derivative, is known to produce tremor through a direct activation of cells in the inferior olive. However, the receptor(s) through which harmaline acts remains unknown. It was recently reported that the tremorogenic actions of harmaline could be blocked by the noncompetitive NMDA channel blocker, MK-801. This study examined whether the blockade of harmaline's action, in the rabbit, by MK-801 was due to a pharmacological antagonism at the MK-801 binding site. This was accomplished by measurement of [3H]MK-801 binding in membrane fractions derived from tissue containing the inferior olivary nucleus and from cerebral cortex. Harmaline completely displaced saturable [3H]MK-801 binding in both the inferior olive and cortex with apparent IC50 values of 60 and 170 microM, respectively. These IC50 values are consistent with the high doses of harmaline required to produce tremor, e.g., 10-30 mg/kg. Non-linear curve fitting analysis of [3H]MK-801 saturation experiments indicated that [3H]MK-801 bound to a single site and that harmaline's displacement of [3H]MK-801 binding to the NMDA receptor was competitive as indicated by a shift in Kd but not in Bmax. In addition, a Schild plot gave a slope that was not significantly different from 1 indicating that harmaline was producing a displacement of [3H]MK-801 from its binding site within the NMDA cation channel and not through an action at the glutamate or other allosteric sites on the NMDA receptor. These findings provide in vitro evidence that the competitive blockade of harmaline-induced tremor by MK-801 occurs within the calcium channel coupled to the NMDA receptor. Our hypothesis is that harmaline produces tremor by acting as an inverse agonist at the MK-801 binding site and thus opening the cation channel.

  2. [11C]CHIBA-1001 as a novel PET ligand for alpha7 nicotinic receptors in the brain: a PET study in conscious monkeys.

    Directory of Open Access Journals (Sweden)

    Kenji Hashimoto

    Full Text Available BACKGROUND: The alpha7 nicotinic acetylcholine receptors (nAChRs play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. However, there are currently no suitable positron emission tomography (PET radioligands for imaging alpha7 nAChRs in the intact human brain. Here we report the novel PET radioligand [11C]CHIBA-1001 for in vivo imaging of alpha7 nAChRs in the non-human primate brain. METHODOLOGY/PRINCIPAL FINDINGS: A receptor binding assay showed that CHIBA-1001 was a highly selective ligand at alpha7 nAChRs. Using conscious monkeys, we found that the distribution of radioactivity in the monkey brain after intravenous administration of [11C]CHIBA-1001 was consistent with the regional distribution of alpha7 nAChRs in the monkey brain. The distribution of radioactivity in the brain regions after intravenous administration of [11C]CHIBA-1001 was blocked by pretreatment with the selective alpha7 nAChR agonist SSR180711 (5.0 mg/kg. However, the distribution of [11C]CHIBA-1001 was not altered by pretreatment with the selective alpha4beta2 nAChR agonist A85380 (1.0 mg/kg. Interestingly, the binding of [11C]CHIBA-1001 in the frontal cortex of the monkey brain was significantly decreased by subchronic administration of the N-methyl-D-aspartate (NMDA receptor antagonist phencyclidine (0.3 mg/kg, twice a day for 13 days; which is a non-human primate model of schizophrenia. CONCLUSIONS/SIGNIFICANCE: The present findings suggest that [11C]CHIBA-1001 could be a novel useful PET ligand for in vivo study of the receptor occupancy and pathophysiology of alpha7 nAChRs in the intact brain of patients with neuropsychiatric diseases such as schizophrenia and Alzheimer's disease.

  3. Simplified PET measurement for evaluating histamine H{sub 1} receptors in human brains using [{sup 11}C]doxepin

    Energy Technology Data Exchange (ETDEWEB)

    Mochizuki, Hideki [Department of Pharmacology, Tohoku University School of Medicine, Sendai, 980-8575 (Japan); Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan); Kimura, Yuichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan)]. E-mail: ukimura@ieee.org; Ishii, Kenji [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan); Oda, Keiichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan); Sasaki, Toru [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan); Tashiro, Manabu [Department of Pharmacology, Tohoku University School of Medicine, Sendai, 980-8575 (Japan); Yanai, Kazuhiko [Department of Pharmacology, Tohoku University School of Medicine, Sendai, 980-8575 (Japan); Ishiwata, Kiichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan)

    2004-11-01

    The aim of this study was to develop simplified positron emission tomography measurement using [{sup 11}C]doxepin ([{sup 11}C]DOX) to evaluate histamine H{sub 1} receptors (H1Rs) in human brains. We evaluated the correlation between the distribution volume (DV) of [{sup 11}C]DOX, estimated quantitatively with a two-compartment model, and the [{sup 11}C]DOX uptake obtained at various time intervals and normalized using the metabolite-corrected plasma radioactivity. We found that the static 70- to 90-min images normalized using the plasma radioactivity at 10 min postinjection reflected the DV of [{sup 11}C]DOX-H1R binding.

  4. Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36

    DEFF Research Database (Denmark)

    Ettrup, Anders; Svarer, Claus; McMahon, Brenda

    2016-01-01

    INTRODUCTION: [(11)C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test-retest variability of cerebral [(11)C]Cimbi-36 PET and compare [(11)C...... test-retest variability in [(11)C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [(18)F]altanserin. Regional differences in the brain distribution of [(11)C]Cimbi-36 and [(18)F]altanserin were assessed with a correlation of regional binding measures...... and with voxel-based analysis. RESULTS: Test-retest variability of [(11)C]Cimbi-36 non-displaceable binding potential (BPND) was consistently correlation between regional...

  5. Effects of white spirits on rat brain 5-HT receptor functions and synaptic remodeling

    DEFF Research Database (Denmark)

    Lam, Henrik Rye; Plenge, P.; Jørgensen, O.S.

    2001-01-01

    Previously, inhalation exposure to different types of white spirit (i.e. complex mixtures of aliphatic, aromatic, alkyl aromatic, and naphthenic hydrocarbons) has been shown to induce neurochemical effects in rat brains. Especially, the serotonergic system was involved at the global, regional, an...

  6. Toll-like receptor 2 signaling in response to brain injury: an innate bridge to neuroinflammation

    DEFF Research Database (Denmark)

    Babcock, Alicia; Wirenfeldt, Martin; Holm, Thomas

    2006-01-01

    -mutant mice. Consistent with the fact that responses in knock-out mice had all returned to wild-type levels by 8 d, there was no evidence for effects on neuronal plasticity at 20 d. These results identify a role for TLR2 signaling in the early glial response to brain injury, acting as an innate bridge...

  7. Effects of swim stress and fluoxetine on 5-HT1A receptor gene expression and monoamine metabolism in the rat brain regions.

    Science.gov (United States)

    Shishkina, G T; Kalinina, T S; Dygalo, N N

    2012-07-01

    Changes in gene expression of the brain serotonin (5-HT) 1A receptors may be important for the development and ameliorating depression, however identification of specific stimuli that activate or reduce the receptor transcriptional activity is far from complete. In the present study, the forced swim test (FST) exposure, the first stress session of which is already sufficient to induce behavioral despair in rats, significantly increased 5-HT1A receptor mRNA levels in the brainstem, frontal cortex, and hippocampus at 24 h. In the brainstem and frontal cortex, the elevation in the receptor gene expression after the second forced swim session was not affected following chronic administration of fluoxetine, while in the cortex, both control and FST values were significantly reduced in fluoxetine-treated rats. In contrast to untreated rats, no increase in hippocampal 5-HT1A receptor mRNA was observed in response to FST in rats chronically treated with fluoxetine. Metabolism of 5-HT (5-HIAA/5-HT) in the brainstem was significantly decreased by fluoxetine and further reduced by swim stress, showing a certain degree of independence of these changes on 5-HT1A receptor gene expression that was increased in this brain region only after the FST, but not after fluoxetine. FST exposure also decreased the brainstem dopamine metabolism, which was unexpectedly positively correlated with 5-HT1A receptor mRNA levels in the frontal cortex. Together, these data suggest that the effects of the forced swim stress as well as fluoxetine involve brain region-dependent alterations in 5-HT1A receptor gene transcription, some of which may be interrelated with concomitant changes in catecholamine metabolism.

  8. Evaluation of MRI and cannabinoid type 1 receptor PET templates constructed using DARTEL for spatial normalization of rat brains

    International Nuclear Information System (INIS)

    Kronfeld, Andrea; Müller-Forell, Wibke; Buchholz, Hans-Georg; Maus, Stephan; Reuss, Stefan; Schreckenberger, Mathias; Miederer, Isabelle; Lutz, Beat

    2015-01-01

    Purpose: Image registration is one prerequisite for the analysis of brain regions in magnetic-resonance-imaging (MRI) or positron-emission-tomography (PET) studies. Diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) is a nonlinear, diffeomorphic algorithm for image registration and construction of image templates. The goal of this small animal study was (1) the evaluation of a MRI and calculation of several cannabinoid type 1 (CB1) receptor PET templates constructed using DARTEL and (2) the analysis of the image registration accuracy of MR and PET images to their DARTEL templates with reference to analytical and iterative PET reconstruction algorithms. Methods: Five male Sprague Dawley rats were investigated for template construction using MRI and [ 18 F]MK-9470 PET for CB1 receptor representation. PET images were reconstructed using the algorithms filtered back-projection, ordered subset expectation maximization in 2D, and maximum a posteriori in 3D. Landmarks were defined on each MR image, and templates were constructed under different settings, i.e., based on different tissue class images [gray matter (GM), white matter (WM), and GM + WM] and regularization forms (“linear elastic energy,” “membrane energy,” and “bending energy”). Registration accuracy for MRI and PET templates was evaluated by means of the distance between landmark coordinates. Results: The best MRI template was constructed based on gray and white matter images and the regularization form linear elastic energy. In this case, most distances between landmark coordinates were <1 mm. Accordingly, MRI-based spatial normalization was most accurate, but results of the PET-based spatial normalization were quite comparable. Conclusions: Image registration using DARTEL provides a standardized and automatic framework for small animal brain data analysis. The authors were able to show that this method works with high reliability and validity. Using DARTEL templates

  9. Opioid receptor imaging and displacement studies with [6-O-[11C]methyl]buprenorphine in baboon brain

    International Nuclear Information System (INIS)

    Galynker, Igor; Schlyer, David J.; Dewey, Stephen L.; Fowler, Joanna S.; Logan, Jean; Gatley, S. John; MacGregor, Robert R.; Ferrieri, Richard A.; Holland, M. J.; Brodie, Jonathan; Simon, Eric; Wolf, Alfred P.

    1996-01-01

    Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[ 11 C]methyl]buprenorphine ([ 11 C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% ± 2.2% and 43% ± 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [ 11 C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal ( 11 C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi

  10. Evaluation of MRI and cannabinoid type 1 receptor PET templates constructed using DARTEL for spatial normalization of rat brains

    Energy Technology Data Exchange (ETDEWEB)

    Kronfeld, Andrea; Müller-Forell, Wibke [Institute of Neuroradiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, Mainz 55131 (Germany); Buchholz, Hans-Georg; Maus, Stephan; Reuss, Stefan; Schreckenberger, Mathias; Miederer, Isabelle, E-mail: isabelle.miederer@unimedizin-mainz.de [Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, Mainz 55131 (Germany); Lutz, Beat [Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, Mainz 55128 (Germany)

    2015-12-15

    Purpose: Image registration is one prerequisite for the analysis of brain regions in magnetic-resonance-imaging (MRI) or positron-emission-tomography (PET) studies. Diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) is a nonlinear, diffeomorphic algorithm for image registration and construction of image templates. The goal of this small animal study was (1) the evaluation of a MRI and calculation of several cannabinoid type 1 (CB1) receptor PET templates constructed using DARTEL and (2) the analysis of the image registration accuracy of MR and PET images to their DARTEL templates with reference to analytical and iterative PET reconstruction algorithms. Methods: Five male Sprague Dawley rats were investigated for template construction using MRI and [{sup 18}F]MK-9470 PET for CB1 receptor representation. PET images were reconstructed using the algorithms filtered back-projection, ordered subset expectation maximization in 2D, and maximum a posteriori in 3D. Landmarks were defined on each MR image, and templates were constructed under different settings, i.e., based on different tissue class images [gray matter (GM), white matter (WM), and GM + WM] and regularization forms (“linear elastic energy,” “membrane energy,” and “bending energy”). Registration accuracy for MRI and PET templates was evaluated by means of the distance between landmark coordinates. Results: The best MRI template was constructed based on gray and white matter images and the regularization form linear elastic energy. In this case, most distances between landmark coordinates were <1 mm. Accordingly, MRI-based spatial normalization was most accurate, but results of the PET-based spatial normalization were quite comparable. Conclusions: Image registration using DARTEL provides a standardized and automatic framework for small animal brain data analysis. The authors were able to show that this method works with high reliability and validity. Using DARTEL

  11. Brain-specific interaction of a 91-kDa membrane-bound protein with the cytoplasmic tail of the 300-kDa mannose 6-phosphate receptor

    DEFF Research Database (Denmark)

    Rosorius, O; Issinger, O G; Braulke, T

    1996-01-01

    The cytoplasmic tail of the 300 kDa mannose 6-phosphate receptor (MPR 300-CT) is thought to play an important role in sorting and targeting of lysosomal enzymes and the insulin-like growth factor II along the biosynthetic and endocytic pathway. In this study a brain specific 91 kDa protein and a ...... in neuronal cells....

  12. Characterization of the glucagon-like peptide-1 receptor in male mouse brain using a novel antibody and in situ hybridization

    DEFF Research Database (Denmark)

    Jensen, Casper Bo; Pyke, Charles; Rasch, Morten Grønbech

    2017-01-01

    was abundantly expressed in numerous regions including the septal nucleus, the hypothalamus and the brain stem. GLP-1R protein expression was also observed on neuronal projections in brain regions devoid of any mRNA which has not been observed in earlier reports. Taken together, these findings provide new......Glucagon-like peptide-1 (GLP-1) is a physiological regulator of appetite and long-acting GLP-1 receptor agonists (GLP-1RA) lower food intake and bodyweight in both human and animal studies. The effects are mediated through brain GLP-1Rs, and several brain nuclei expressing the GLP-1R may...... be involved. To date, mapping the complete location of GLP-1R protein in the brain has been challenged by lack of good antibodies and the discrepancy between mRNA and protein especially relevant in neuronal axonal processes. Here, we present a novel and specific monoclonal GLP-1R antibody...

  13. Specific in vivo binding in the rat brain of [18F]RP 62203: A selective 5-HT2A receptor radioligand for positron emission tomography

    International Nuclear Information System (INIS)

    Besret, Laurent; Dauphin, Francois; Huard, Cecile; Lasne, Marie-Claire; Vivet, Richard; Mickala, Patrick; Barbelivien, Alexandra; Baron, Jean-Claude

    1996-01-01

    In vivo pharmacokinetic and brain binding characteristics of [ 18 F]RP 62203, a selective high-affinity serotonergic 5-HT 2A receptor antagonist, were assessed in the rat following intravenous injection of trace amount of the radioligand. The radioactive distribution profile observed in the brain 60 min after injection was characterized by greater than fourfold higher uptake in neocortex as compared to cerebellum (0.38 ± 0.07% injected dose/g, % ID/g and 0.08 ± 0.01 ID/g, respectively), consistent with in vivo specific binding to the 5-HT 2A receptor. Furthermore, specific [ 18 F]RP 62203 binding significantly correlated with the reported in vitro distribution of 5-HT 2A receptors, but not with known concentration profiles of dopaminergic D 2 or adrenergic α 1 receptors. Finally, detectable specific binding was abolished by pretreatment with large doses of ritanserin, a selective 5-HT 2A antagonist, which resulted in uniform uptakes across cortical, striatal and cerebellar tissues. Thus, [ 18 F]RP 62203 appears to be a promising selective tool to visualize and quantify 5-HT 2A brain receptors in vivo with positron emission tomography

  14. Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat.

    Science.gov (United States)

    Wong, Yin Cheong; Ilkova, Trayana; van Wijk, Rob C; Hartman, Robin; de Lange, Elizabeth C M

    2018-01-01

    Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to occupy the available D2 receptors and antagonize the action of dopamine or drugs on D2 in preclinical studies. The aims of this study were to comprehensively evaluate its pharmacokinetic (PK) profiles in different brain compartments and to establish a PK-RO model that could predict the brain distribution and RO of raclopride in the freely moving rat using a LC-MS based approach. Rats (n=24) received a 10-min IV infusion of non-radiolabeled raclopride (1.61μmol/kg, i.e. 0.56mg/kg). Plasma and the brain tissues of striatum (with high density of D2 receptors) and cerebellum (with negligible amount of D2 receptors) were collected. Additional microdialysis experiments were performed in some rats (n=7) to measure the free drug concentration in the extracellular fluid of the striatum and cerebellum. Raclopride concentrations in all samples were analyzed by LC-MS. A population PK-RO model was constructed in NONMEM to describe the concentration-time profiles in the unbound plasma, brain extracellular fluid and brain tissue compartments and to estimate the RO based on raclopride-D2 receptor binding kinetics. In plasma raclopride showed a rapid distribution phase followed by a slower elimination phase. The striatum tissue concentrations were consistently higher than that of cerebellum tissue throughout the whole experimental period (10-h) due to higher non-specific tissue binding and D2 receptor binding in the striatum. Model-based simulations accurately predicted the literature data on rat plasma PK, brain tissue PK and D2 RO at different time points after intravenous or subcutaneous administration of raclopride at tracer dose (RO 30%). For the first time a predictive model that could describe

  15. (/sup 3/H)Spiperone binding sites in brain: autoradiographic localization of multiple receptors

    Energy Technology Data Exchange (ETDEWEB)

    Palacios, J M; Niehoff, D L; Kuhar, M J [Johns Hopkins Univ., Baltimore, MD (USA). School of Medicine

    1981-01-01

    (/sup 3/H)Spiperone ((/sup 3/H)SP) binding sites were localized by light microscopic autoradiography, after in vitro labelling. The kinetic and pharmacological characteristics of these binding sites were studied in slide-mounted sections of rat forebrain, and optimal labeling conditions were defined. Autoradiograms were obtained by apposing emulsion-coated coverslips to labeled sections. Differential drug sensitivity allowed the selective displacement of (/sup 3/H)SP from dopamine receptors by ADTN, from serotonin receptors by cinanserin, from both by haloperidol and from unique spiperone sites by unlabeled spiperone. The various sites presented a differential anatomical localization. For example, only dopaminergic sites were found in the glomerular layer of the olfactory bulb; only serotonergic sites were found in lamina IV of the neocortex, and a high concentration of unique spiperone sites were found in parts of the hippocampus.

  16. Effect of thyrotrophin releasing hormone on opiate receptors of the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Balashov, A.M.; Shchurin, M.R.

    1987-01-01

    It has recently been shown that the hypothalamic thyrotropin releasing hormone (TRH) has the properties of a morphine antagonist, blocking its inhibitory action on respiration and, to a lesser degree, its analgesic action. This suggests that the antagonistic effects of TRH are mediated through its interaction with opiate receptors. The aim of this paper is to study this hypothesis experimentally. Tritium-labelled enkephalins in conjunction with scintillation spectroscopy were used to assess the receptor binding behavior. The results indicate the existence of interconnections between the opiate systems and TRH. Although it is too early to reach definite conclusions on the mechanisms of this mutual influence and its physiological significance it can be tentatively suggested that TRH abolishes the pharmacological effects of morphine by modulating the functional state of opiate reception.

  17. Receptor binding of somatostatin-14 and somatostatin-28 in rat brain: differential modulation by nucleotides and ions.

    Science.gov (United States)

    Srikant, C B; Dahan, A; Craig, C

    1990-02-04

    The tissue-selective binding of the two principal bioactive forms of somatostatin, somatostatin-14 (SS-14) and somatostatin-28 (SS-28), their ability to modulate cAMP-dependent and -independent regulation of post-receptor events to different degrees and the documentation of specific labelling of SS receptor subtypes with SS-28 but not SS-14 in discrete regions of rat brain suggest the existence of distinct SS-14 and SS-28 binding sites. Receptor binding of SS-14 ligands has been shown to be modulated by nucleotides and ions, but the effect of these agents on SS-28 binding has not been studied. In the present study we investigated the effects of adenine and guanine nucleotides as well as monovalent and divalent cations on rat brain SS receptors quantitated with radioiodinated analogs of SS-14 ([125I-Tyr11]SS14, referred to in this paper as SS-14) and SS-28 ([Leu8, D-Trp22, 125I-Tyr25] SS-28, referred to as LTT* SS-28) in order to determine if distinct receptor sites for SS-14 and SS-28 could be distinguished on the basis of their modulation by nucleotides and ions. GTP as well as ATP exerted a dose-dependent inhibition (over a concentration range of 10(-7)-10(-3) M) of the binding of the two radioligands. The nucleotide inhibition of binding resulted in a decrease the Bmax of the SS receptors, the binding affinity remaining unaltered. GTP (10(-4) M) decreased the Bmax of LTT* SS-28 binding sites to a greater extent than ATP (145 +/- 10 and 228 +/- 16 respectively, compared to control value of 320 +/- 20 pmol mg-1). Under identical conditions GTP was less effective than ATP in reducing the number of T* SS-14 binding sites (Bmax = 227 +/- 8 and 182 +/- 15, respectively, compared to 340 +/- 15 pmol mg-1 in the absence of nucleotides). Monovalent cations inhibited the binding of both radioligands, Li+ and Na+ inhibited the binding of T* SS-14 to a greater extent than K+. The effect of divalent cations on the other hand was varied. At low concentration (2 mM) Mg2+, Ba2

  18. Brain nicotinic acetylcholine receptors are involved in stress-induced potentiation of nicotine reward in rats.

    Science.gov (United States)

    Javadi, Parastoo; Rezayof, Ameneh; Sardari, Maryam; Ghasemzadeh, Zahra

    2017-07-01

    The aim of the present study was to examine the possible role of nicotinic acetylcholine receptors of the dorsal hippocampus (CA1 regions), the medial prefrontal cortex or the basolateral amygdala in the effect of acute or sub-chronic stress on nicotine-induced conditioned place preference. Our results indicated that subcutaneous administration of nicotine (0.2 mg/kg) induced significant conditioned place preference. Exposure to acute or sub-chronic elevated platform stress potentiated the response of an ineffective dose of nicotine. Pre-conditioning intra-CA1 (0.5-4 µg/rat) or intra-medial prefrontal cortex (0.2-0.3 µg/rat) microinjection of mecamylamine (a non-selective nicotinic acetylcholine receptor antagonist) reversed acute stress-induced potentiation of nicotine reward as measured in the conditioned place preference paradigm. By contrast, pre-conditioning intra-basolateral amygdala microinjection of mecamylamine (4 µg/rat) potentiated the effects of acute stress on nicotine reward. Our findings also showed that intra-CA1 or intra-medial prefrontal cortex, but not intra-basolateral amygdala, microinjection of mecamylamine (4 µg/rat) prevented the effect of sub-chronic stress on nicotine reward. These findings suggest that exposure to elevated platform stress potentiates the rewarding effect of nicotine which may be associated with the involvement of nicotinic acetylcholine receptors. It seems that there is a different contribution of the basolateral amygdala, the medial prefrontal cortex or the CA1 nicotinic acetylcholine receptors in stress-induced potentiation of nicotine-induced conditioned place preference.

  19. Revisiting nanoparticle technology for blood-brain barrier transport: Unfolding at the endothelial gate improves the fate of transferrin receptor-targeted liposomes.

    Science.gov (United States)

    Johnsen, Kasper Bendix; Moos, Torben

    2016-01-28

    An unmet need exists for therapeutic compounds to traverse the brain capillary endothelial cells that denote the blood-brain barrier (BBB) to deliver effective treatment to the diseased brain. The use of nanoparticle technology for targeted delivery to the brain implies that targeted liposomes encapsulating a drug of interest will undergo receptor-mediated uptake and transport through the BBB with a subsequent unfolding of the liposomal content inside the brain, hence revealing drug release to adjacent drug-demanding neurons. As transferrin receptors (TfRs) are present on brain capillary endothelial, but not on endothelial cells elsewhere in the body, the use of TfR-targeted liposomes - colloidal particulates with a phospholipid bilayer membrane - remains the most relevant strategy to obtain efficient drug delivery to the brain. However, many studies have failed to provide sufficient quantitative data to proof passage of the BBB and significant appearance of drugs inside the brain parenchyma. Here, we critically evaluate the current evidence on the use of TfR-targeted liposomes for brain drug delivery based on a thorough investigation of all available studies within this research field. We focus on issues with respect to experimental design and data analysis that may provide an explanation to conflicting reports, and we discuss possible explanations for the current lack of sufficient transcytosis across the BBB for implementation in the design of TfR-targeted liposomes. We finally provide a list of suggestions for strategies to obtain substantial uptake and transport of drug carriers at the BBB with a concomitant transport of therapeutics into the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Changes in Glutamate/NMDA Receptor Subunit 1 Expression in Rat Brain after Acute and Subacute Exposure to Methamphetamine

    Directory of Open Access Journals (Sweden)

    Walailuk Kerdsan

    2009-01-01

    Full Text Available Methamphetamine (METH is a psychostimulant drug of abuse that produces long-term behavioral changes including behavioral sensitization, tolerance, and dependence. METH has been reported to induce neurotoxic effects in several areas of the brain via the dopaminergic system. Changes of dopamine function can induce malfunction of the glutamatergic system. Therefore, the aim of the present study was to examine the effects of METH administration on the expression of glutamate N-methyl-D-aspartate receptor subunit 1 (NMDAR1 in frontal cortex, striatum, and hippocampal formation after acute and subacute exposure to METH by western blotting. Male Sprague-Dawley rats were injected intraperitoneally with a single dose of 8 mg/kg METH, 4 mg/kg/day METH for 14 days and saline in acute, subacute, and control groups, respectively. A significant increase in NMDAR1 immunoreactive protein was found in frontal cortex in the subacute group (P=.036 but not in the acute group (P=.580. Moreover, a significant increase in NMDAR1 was also observed in striatum in both acute (P=.025 and subacute groups (P=.023. However, no significant differences in NMDAR1 in hippocampal formation were observed in either acute or subacute group. The results suggest that an upregulation of NMDA receptor expression may be a consequence of glutamatergic dysfunction induced by METH.

  1. Hormonal regulation of steroid receptor coactivator-1 mRNA in the male and female green anole brain.

    Science.gov (United States)

    Kerver, H N; Wade, J

    2015-03-01

    Green anole lizards are seasonal breeders, with male sexual behaviour primarily regulated by an annual increase in testosterone. Morphological, biochemical and behavioural changes associated with reproduction are activated by testosterone, generally with a greater effect in the breeding season (BS) than in the nonbreeding season (NBS). The present study investigates the possibility that differences in a steroid receptor coactivator may regulate this seasonal difference in responsiveness to testosterone. In situ hybridisation was used to examine the expression of steroid receptor coactivator-1 (SRC-1) in the brains of gonadally intact male and female green anoles across breeding states. A second experiment examined gonadectomised animals with and without testosterone treatment. Gonadally intact males had more SRC-1 expressing cells in the preoptic area and larger volumes of this region as defined by these cells than females. Main effects of both sex and season (males > females and BS > NBS) were present in cell number and volume of the ventromedial hypothalamus. An interaction between sex and season suggested that high expression in BS males was driving these effects. In hormone-manipulated animals, testosterone treatment increased both the number of SRC-1 expressing cells in and volumes of the preoptic area and amygdala. These results suggest that testosterone selectively regulates SRC-1, and that this coactivator may play a role in facilitating reproductive behaviours across both sexes. However, changes in SRC-1 expression are not likely responsible for the seasonal change in responsiveness to testosterone. © 2014 British Society for Neuroendocrinology.

  2. A carnivore species (Canis familiaris) expresses circadian melatonin rhythm in the peripheral blood and melatonin receptors in the brain

    International Nuclear Information System (INIS)

    Stankov, B.; Moeller, M.; Lucini, V.; Capsono, S.; Fraschini, F.

    1994-01-01

    Dogs kept under controlled photoperiodic conditions of 12h light and 12h dark expressed a clear diurnal melatonin rhythm in the peripheral blood, with a swift peak restricted to the late part of the scotophase. The highest density of high-affinity, G-protein-linked 2-[ 125 I]iodomelatonin binding sites was found in the pars tuberalis of the pituitary gland. Binding sites were found also in the pars distalis, and light microscopy/high-resolution autoradiography showed that binding was located exclusively over the chromophobe and basophilic cells forming the adenopituitary zona tuberalis, well developed in the species, and extending into the gland as a continuation of pars tuberalis. Cords of basophilic cells located in the pars distalis proper also expressed high receptor density. Quantitative autoradiography inhibition experiments revealed that the apparent melatonin inhibitory constant in all those areas was around 0.1 nmol/l, which is a physiologically appropriate value considering the peripheral blood melatonin levels. Co-incubation with guanosine 3-thiotriphosphate led to a consequential decrease in the binding density. Collectively, these data show that the dog possesses all the prerequisites for an efficient network adapted to photoperiodic time measurements. A circadian melatonin signal in the peripheral blood and an apparently functional readout receptor system located in key positions within the brain are both present in this species. 43 refs. 6 figs., 1 tabs

  3. Region-specific associations between sex, social status, and oxytocin receptor density in the brains of eusocial rodents.

    Science.gov (United States)

    Mooney, S J; Coen, C W; Holmes, M M; Beery, A K

    2015-09-10

    Naturally occurring variations in neuropeptide receptor distributions in the brain contribute to numerous mammalian social behaviors. In naked mole-rats, which live in large social groups and exhibit remarkable reproductive skew, colony-related social behaviors vary with reproductive status. Here we examined whether variation in social status is associated with variations in the location and/or density of oxytocin binding in this species. Autoradiography was performed to assess forebrain oxytocin receptor (OTR) densities in breeding and non-breeding naked mole-rats of both sexes. Overall, males exhibited higher OTR binding in the medial amygdala in comparison to females. While there were no main effects of reproductive status in any region, a sex difference in OTR binding in the nucleus accumbens was mediated by status. Specifically, breeding males tended to have more OTR binding than breeding females in the nucleus accumbens, while no sex difference was observed in subordinates. These effects suggest that oxytocin may act in a sex- and region-specific way that corresponds to reproductive status and associated social behaviors. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Characterization of a purified nicotinic receptor from rat brain by using idiotypic and anti-idiotypic antibodies

    International Nuclear Information System (INIS)

    Abood, L.G.; Langone, J.J.; Bjercke, R.; Lu, X.; Banerjee, S.

    1987-01-01

    The availability of an anti-nicotine monoclonal antibody has made it possible to further establish the nature of the nicotine recognition proteins purified from rat brain by affinity chromatography and to provide a highly sensitive assay for determining [ 3 H]nicotine binding to the purified material. An enantiomeric analogue of nicotine. (-)-6-hydroxymethylnicotine, was used to prepare the affinity column. In addition, with the use of an anti-idiotypic monoclonal antibody, it was confirmed that the recognition site for nicotine resides on a protein complex composed of two components with molecular masses of 62 and 57 kDa. It was also demonstrated that the same two proteins could be purified by immunoaffinity chromatography with the use of an anti-idiotypic monoclonal antibody. With the use of the anti-nicotine antibody to measure [ 3 H]nicotine binding, the purified material was shown to bind 250 pmol/mg of protein. By utilizing a procedure in which the purified receptor protein was conjugated to membranes by disulfide bonds, a binding activity of 80 pmol/mg was obtained. With the availability of sterospecific monoclonal antibodies to (-)-nicotine as well as monoclonal anti-idiotypic antibodies derived when the anti-nicotine antibodies were used as immunogens, additional procedures became available for the further characterization of the purified nicotine receptor and examining its (-)-[ 3 H]nicotine-binding characteristics

  5. ( sup 3 H)opipramol labels a novel binding site and sigma receptors in rat brain membranes

    Energy Technology Data Exchange (ETDEWEB)

    Ferris, C.D.; Hirsch, D.J.; Brooks, B.P.; Snowman, A.M.; Snyder, S.H. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (USA))

    1991-02-01

    Opipramol (OP), a clinically effective antidepressant with a tricyclic structure, is inactive as an inhibitor of biogenic amine uptake. ({sup 3}H)Opipramol binds saturably to rat brain membranes (apparent KD = 4 nM, Bmax = 3 pmol/mg of protein). ({sup 3}H)Opipramol binding can be differentiated into haloperidol-sensitive and -resistant components, with Ki values for haloperidol of 1 nM (Bmax = 1 pmol/mg of protein) and 350 nM (Bmax = 1.9 pmol/mg of protein), respectively. The drug specificity of the haloperidol-sensitive component is the same as that of sigma receptors labeled with (+)-({sup 3}H)3-(3-hydroxyphenyl)-N-(1-propyl)piperdine. The haloperidol-resistant component does not correspond to any known neurotransmitter receptor or uptake recognition site. It displays high affinity for phenothiazines and related structures such as perphenazine, clopenthixol, and flupenthixol, whose potencies are comparable to that of opipramol. Because certain of these drugs are more potent at the haloperidol-resistant opipramol site than in exerting any other action, it is possible that this opipramol-selective site may mediate their therapeutic effects.

  6. The effect of α-, β-adrenergic receptor agonists and antagonists of the efflux of 22Na and uptake of 42K by rat brain cortical slices

    International Nuclear Information System (INIS)

    Phillis, J.W.; Wu, P.H.; Thierry, D.L.

    1982-01-01

    The effects of norepinephrine on ion fluxes in rat brain cortical slices have now been ascertained. 22 Na efflux and 42 K influx are enhanced by norepinephrine. The increase in ion fluxes can be blocked by ouabain, phentolamine and propranolol, suggesting that the catecholamine activates a membrane sodium pump by a receptor-mediated step. The facilitation of 22 Na efflux is stereospecific as demonstrated by the very weak action of D-norepinephrine at 10 -5 M concentration. Various α-adrenergic and β-adrenergic receptor agonists, including oxymetazoline, naphazoline, clonidine, tramazoline, methoxamine, phenylephrine, L-isoproterenol and methoxyphenamine are potent stimulants of the sodium pump as demonstrated by their enhancement of ion fluxes in rat brain cortical slices. The results are consistent with the hypothesis that norepinephrine hyperpolarizes central neurons by activating an ouabain-sensitive, receptor-mediated sodium pump. (Auth.)

  7. Autoradiographic visualization of A 1-adenosine receptors in brain and peripheral tissues of rat and guinea pig using 125I-HPIA

    International Nuclear Information System (INIS)

    Weber, R.G.; Lohse, M.J.; Jones, C.R.; Palacios, J.M.

    1988-01-01

    A 1 -adenosine receptors were identified in sections of rat brain and guinea pig kidney with the radioiodinated agonist 1 25I-N 6 -p-hydroxyphenylisopropyladenosine ( 1 25I-HPIA) using in vitro autoradiography. The affinities of adenosine receptor ligands in competing with 1 25I-HPIA binding to tissue sections were in good agreement with those found in membranes and indicate that the binding site represents an A 1 pattern of [ 3 H]N 6 -cyclohexyladenosine ([ 3 H]CHA) binding sites determined previously, with highest densities in the hippocampus and dentate gyrus, the cerebellar cortex, some thalamic nuclei and certain layers of the cerebral cortex. In the guinea pig kidney 1 25I-HPIA labelled longitudinal structures in the medulla. This study demonstrates that 1 25I-HPIA allows the autoradiographic detection of A-1 adenosine receptors in the brain and peripheral organs and has the advantage of short exposure times (author)

  8. Autoradiographic localization of adenosine A1 receptors in rat brain using [3H]XCC, a functionalized congener of 1,3-dipropylxanthine

    International Nuclear Information System (INIS)

    Jarvis, M.J.; Williams, M.; Jacobson, K.A.

    1987-01-01

    Quantitative autoradiography was used to visualize the anatomical distribution of adenosine receptors labeled by the carboxylic acid congener of 1,3-dipropylxanthine, [ 3 Hi](8-(p-carbonxymethyloxy) phenyl-1,3 dipropylxanthine)([ 3 H]XCC) in rat brain. [ 3 H]XCC was observed to specifically bind to rat brain sagittal sections in a heterogenous pattern. Saturation experiments revealed that [ 3 H]XCC binds with nanomolar affinity to 20μm frozen tissue sections with the highest binding densities occurring in the hippocampus and cerebellum. Both the binding characteristics and regional receptor distribution obtained with [ 3 H]XCC demonstrate the potential usefulness of this new ligand in the study of adenosine A 1 receptors. 13 refs. (Author)

  9. Immunolocalization of the short neuropeptide F receptor in queen brains and ovaries of the red imported fire ant (Solenopsis invicta Buren

    Directory of Open Access Journals (Sweden)

    Pietrantonio Patricia V

    2011-06-01

    Full Text Available Abstract Background Insect neuropeptides are involved in diverse physiological functions and can be released as neurotransmitters or neuromodulators acting within the central nervous system, and as circulating neurohormones in insect hemolymph. The insect short neuropeptide F (sNPF peptides, related to the vertebrate neuropeptide Y (NPY peptides, have been implicated in the regulation of food intake and body size, and play a gonadotropic role in the ovaries of some insect species. Recently the sNPF peptides were localized in the brain of larval and adult Drosophila. However, the location of the sNPF receptor, a G protein-coupled receptor (GPCR, has not yet been investigated in brains of any adult insect. To elucidate the sites of action of the sNPF peptide(s, the sNPF receptor tissue expression and cellular localization were analyzed in queens of the red imported fire ant, Solenopsis invicta Buren (Hymenoptera, an invasive social insect. Results In the queen brains and subesophageal ganglion about 164 cells distributed in distinctive cell clusters (C1-C9 and C12 or as individual cells (C10, C11 were immuno-positive for the sNPF receptor. Most of these neurons are located in or near important sensory neuropils including the mushroom bodies, the antennal lobes, the central complex, and in different parts of the protocerebrum, as well as in the subesophageal ganglion. The localization of the sNPF receptor broadly links the receptor signaling pathway with circuits regulating learning and feeding behaviors. In ovaries from mated queens, the detection of sNPF receptor signal at the posterior end of oocytes in mid-oogenesis stage suggests that the sNPF signaling pathway may regulate processes at the oocyte pole. Conclusions The analysis of sNPF receptor immunolocalization shows that the sNPF signaling cascade may be involved in diverse functions, and the sNPF peptide(s may act in the brain as neurotransmitter(s or neuromodulator(s, and in the ovaries

  10. Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria.

    Directory of Open Access Journals (Sweden)

    Wei Zheng

    2010-12-01

    Full Text Available Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic ligand 2-methylthioladenosine 5' diphosphate (2-MeSADP, an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y(1R. At 24 hours, cytotoxic edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the infarct. Delayed 2MeSADP treatment, 24 hours after the initial thrombosis, also significantly reduced cytotoxic edema and the continued growth of the brain infarction. Pharmacological and genetic evidence are presented indicating that 2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased inositol trisphosphate (IP(3-dependent Ca(2+ release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low ATP levels are widely accepted to be responsible for cytotoxic edema. Enhancement of this energy source could have similar protective benefits for a wide range of brain injuries.

  11. Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia.

    Science.gov (United States)

    Dalwadi, Dhwanil A; Kim, Seongcheol; Schetz, John A

    2017-05-01

    Glial cells play a critical role in neuronal support which includes the production and release of the neurotrophin brain-derived neurotrophic factor (BDNF). Activation of the sigma-1 receptor (S1R) has been shown to attenuate inflammatory stress-mediated brain injuries, and there is emerging evidence that this may involve a BDNF-dependent mechanism. In this report we studied S1R-mediated BDNF release from human astrocytic glial cells. Astrocytes express the S1R, which mediates BDNF release when stimulated with the prototypical S1R agonists 4-PPBP and (+)-SKF10047. This effect could be antagonized by a selective concentration of the S1R antagonist BD1063. Haloperidol is known to have high affinity interactions with the S1R, yet it was unable to facilitate BDNF release. Remarkably, however, two metabolites of haloperidol, haloperidol I and haloperidol II (reduced haloperidol), were discovered to facilitate BDNF secretion and this effect was antagonized by BD1063. Neither 4-PPBP, nor either of the haloperidol metabolites affected the level of BDNF mRNA as assessed by qPCR. These results demonstrate for the first time that haloperidol metabolites I and II facilitate the secretion of BDNF from astrocytes by acting as functionally selective S1R agonists. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

    Energy Technology Data Exchange (ETDEWEB)

    Teeguarden, Justin G.; Housand, Conrad; Smith, Jordan N.; Hinderliter, Paul M.; Gunawan, Rudy; Timchalk, Charles

    2013-02-01

    The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.

  13. Assessment of {alpha}7 nicotinic acetylcholine receptor availability in juvenile pig brain with [{sup 18}F]NS10743

    Energy Technology Data Exchange (ETDEWEB)

    Deuther-Conrad, Winnie; Fischer, Steffen; Hiller, Achim; Funke, Uta; Brust, Peter [Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmacy, Leipzig (Germany); Becker, Georg; Sabri, Osama [Univ. of Leipzig, Dept. of Nuclear Medicine, Leipzig (Germany); Cumming, Paul; Xiong, Guoming [Univ. of Munich, Dept. of Nuclear Medicine, Munich (Germany); Peters, Dan [NeuroSearch A/S, Ballerup (Denmark)

    2011-08-15

    To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [{sup 18}F]NS10743, a novel diazabicyclononane derivative targeting {alpha}7 nicotinic acetylcholine receptors ({alpha}7 nAChRs). Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [{sup 18}F]NS10743 under baseline conditions (n = 3) and after blocking of the {alpha}7 nAChR with NS6740 (3 mg.kg{sup -1} bolus + 1 mg.kg{sup -1}.h{sup -1} continuous infusion; n = 3). Arterial plasma samples were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time-radioactivity curves was performed, and parametric maps were calculated relative to arterial input. Plasma [{sup 18}F]NS10743 passed readily into the brain, with peak uptake occurring in {alpha}7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippocampus. The highest SUV{sub max} was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUV{sub max} 1.53 {+-} 0.32). Administration of NS6740 significantly decreased [{sup 18}F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BP{sub ND}. The baseline BP{sub ND} ranged from 0.39 {+-} 0.08 in the cerebellum to 0.76 {+-} 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BP{sub ND} in regions with high [{sup 18}F]NS10743 binding (temporal lobe -29%, p = 0.01; midbrain: -35%, p = 0.02), without significantly altering the BP{sub ND} in low binding regions (cerebellum: -16%, p = 0.2). This study confirms the potential of [{sup 18}F]NS10743 as a target-specific radiotracer for the molecular imaging of central {alpha}7 nAChRs by PET. (orig.)

  14. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier.

    Science.gov (United States)

    Molino, Yves; David, Marion; Varini, Karine; Jabès, Françoise; Gaudin, Nicolas; Fortoul, Aude; Bakloul, Karima; Masse, Maxime; Bernard, Anne; Drobecq, Lucile; Lécorché, Pascaline; Temsamani, Jamal; Jacquot, Guillaume; Khrestchatisky, Michel

    2017-05-01

    The blood-brain barrier (BBB) prevents the entry of many drugs into the brain and, thus, is a major obstacle in the treatment of CNS diseases. There is some evidence that the LDL receptor (LDLR) is expressed at the BBB and may participate in the transport of endogenous ligands from blood to brain, a process referred to as receptor-mediated transcytosis. We previously described a family of peptide vectors that were developed to target the LDLR. In the present study, in vitro BBB models that were derived from wild-type and LDLR-knockout animals ( ldlr -/- ) were used to validate the specific LDLR-dependent transcytosis of LDL via a nondegradative route. We next showed that LDLR-targeting peptide vectors, whether in fusion or chemically conjugated to an Ab Fc fragment, promote binding to apical LDLR and transendothelial transfer of the Fc fragment across BBB monolayers via the same route as LDL. Finally, we demonstrated in vivo that LDLR significantly contributes to the brain uptake of vectorized Fc. We thus provide further evidence that LDLR is a relevant receptor for CNS drug delivery via receptor-mediated transcytosis and that the peptide vectors we developed have the potential to transport drugs, including proteins or Ab based, across the BBB.-Molino, Y., David, M., Varini, K., Jabès, F., Gaudin, N., Fortoul, A., Bakloul, K., Masse, M., Bernard, A., Drobecq, L., Lécorché, P., Temsamani, J., Jacquot, G., Khrestchatisky, M. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier. © FASEB.

  15. Hormonally-mediated Epigenetic Changes to Steroid Receptors in the Developing Brain: Implications for Sexual Differentiation

    OpenAIRE

    Nugent, Bridget M.; Schwarz, Jaclyn M.; McCarthy, Margaret M.

    2010-01-01

    The establishment of sex-specific neural morphology, which underlies sex-specific behaviors, occurs during a perinatal sensitive window in which brief exposure to gonadal steroid hormones produces permanent masculinization of the brain. In the rodent, estradiol derived from testicular androgens is a principle organizational hormone. The mechanism by which transient estradiol exposure induces permanent differences in neuronal anatomy has been widely investigated, but remains elusive. Epigeneti...

  16. Selective Toll-Like Receptor 4 Antagonists Prevent Acute Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice.

    Science.gov (United States)

    Okada, Takeshi; Kawakita, Fumihiro; Nishikawa, Hirofumi; Nakano, Fumi; Liu, Lei; Suzuki, Hidenori

    2018-05-31

    There are no direct evidences showing the linkage between Toll-like receptor 4 (TLR4) and blood-brain barrier (BBB) disruption after subarachnoid hemorrhage (SAH). The purpose of this study was to examine if selective blockage of TLR4 prevents BBB disruption after SAH in mice and if the TLR4 signaling involves mitogen-activated protein kinases (MAPKs). One hundred and fifty-one C57BL/6 male mice underwent sham or endovascular perforation SAH operation, randomly followed by an intracerebroventricular infusion of vehicle or two dosages (117 or 585 ng) of a selective TLR4 antagonist IAXO-102 at 30 min post-operation. The effects were evaluated by survival rates, neurological scores, and brain water content at 24-72 h and immunoglobulin G immunostaining and Western blotting at 24 h post-SAH. IAXO-102 significantly prevented post-SAH neurological impairments, brain edema, and BBB disruption, resulting in improved survival rates. IAXO-102 also significantly suppressed post-SAH activation of a major isoform of MAPK p46 c-Jun N-terminal kinase (JNK) and matrix metalloproteinase-9 as well as periostin induction and preserved tight junction protein zona occludens-1. Another selective TLR4 antagonist TAK-242, which has a different binding site from IAXO-102, also showed similar effects to IAXO-102. This study first provided the evidence that TLR4 signaling is involved in post-SAH acute BBB disruption and that the signaling is mediated at least partly by JNK activation. TLR4-targeted therapy may be promising to reduce post-SAH morbidities and mortalities.

  17. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity.

    Science.gov (United States)

    Hammer, C; Stepniak, B; Schneider, A; Papiol, S; Tantra, M; Begemann, M; Sirén, A-L; Pardo, L A; Sperling, S; Mohd Jofrry, S; Gurvich, A; Jensen, N; Ostmeier, K; Lühder, F; Probst, C; Martens, H; Gillis, M; Saher, G; Assogna, F; Spalletta, G; Stöcker, W; Schulz, T F; Nave, K-A; Ehrenreich, H

    2014-10-01

    In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function.

  18. Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes.

    Science.gov (United States)

    Daskalakis, Nikolaos P; Cohen, Hagit; Cai, Guiqing; Buxbaum, Joseph D; Yehuda, Rachel

    2014-09-16

    Delineating the molecular basis of individual differences in the stress response is critical to understanding the pathophysiology and treatment of posttraumatic stress disorder (PTSD). In this study, 7 d after predator-scent-stress (PSS) exposure, male and female rats were classified into vulnerable (i.e., "PTSD-like") and resilient (i.e., minimally affected) phenotypes on the basis of their performance on a variety of behavioral measures. Genome-wide expression profiling in blood and two limbic brain regions (amygdala and hippocampus), followed by quantitative PCR validation, was performed in these two groups of animals, as well as in an unexposed control group. Differentially expressed genes were identified in blood and brain associated with PSS-exposure and with distinct behavioral profiles postexposure. There was a small but significant between-tissue overlap (4-21%) for the genes associated with exposure-related individual differences, indicating convergent gene expression in both sexes. To uncover convergent signaling pathways across tissue and sex, upstream activated/deactivated transcription factors were first predicted for each tissue and then the respective pathways were identified. Glucocorticoid receptor (GR) signaling was the only convergent pathway associated with individual differences when using the most stringent statistical threshold. Corticosterone treatment 1 h after PSS-exposure prevented anxiety and hyperarousal 7 d later in both sexes, confirming the GR involvement in the PSS behavioral response. In conclusion, genes and pathways associated with extreme differences in the traumatic stress behavioral response can be distinguished from those associated with trauma exposure. Blood-based biomarkers can predict aspects of brain signaling. GR signaling is a convergent signaling pathway, associated with trauma-related individual differences in both sexes.

  19. In vitro assessment of the agonist properties of the novel 5-HT1A receptor ligand, CUMI-101 (MMP), in rat brain tissue

    International Nuclear Information System (INIS)

    Hendry, Nicola; Christie, Isabel; Rabiner, Eugenii Alfredovich; Laruelle, Marc; Watson, Jeannette

    2011-01-01

    Introduction: Development of agonist positron emission tomography (PET) radioligands for the 5-HT neurotransmitter system is an important target to enable the understanding of human 5-HT function in vivo. [ 11 C]CUMI-101, proposed as the first 5-HT 1A receptor agonist PET ligand, has been reported to behave as a potent 5-HT 1A agonist in a cellular system stably expressing human recombinant 5-HT 1A receptors. In this study, we investigate the agonist properties of CUMI-101 in rat brain tissue. Methods: [ 35 S]-GTPγS binding studies were used to determine receptor function in HEK (human embryonic kidney) 293 cells transfected with human recombinant 5-HT 1A receptors and in rat cortex and rat hippocampal tissue, following administration of CUMI-101 and standard 5-HT1A antagonists (5-HT, 5-CT and 8-OH-DPAT). Results: CUMI-101 behaved as an agonist at human recombinant 5-HT 1A receptors (pEC 50 9.2). However, CUMI-101 did not show agonist activity in either rat cortex or hippocampus at concentrations up to 10 μM. In these tissues, CUMI-behaved as an