ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functional Effects in the Brain after Systemic Dosing
Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendoc...
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| creator | Alfinito, Peter D Chen, Xiaohong Atherton, James Cosmi, Scott Deecher, Darlene C |
| description | Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg·d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 α-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg·d) dose dependently inhibited this effect. ICI (3.0 mg/kg·d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg·d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg·d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions. |
| doi_str_mv | 10.1210/en.2008-0532 |
| format | Article |
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However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg·d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 α-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg·d) dose dependently inhibited this effect. ICI (3.0 mg/kg·d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg·d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg·d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2008-0532</identifier><identifier>PMID: 18599545</identifier><identifier>CODEN: ENDOAO</identifier><language>eng</language><publisher>Bethesda, MD: Endocrine Society</publisher><subject>17β-Estradiol ; Animals ; Antiestrogens ; Biological and medical sciences ; Blood-brain barrier ; Blood-Brain Barrier - metabolism ; Body temperature ; Body weight ; Body Weight - drug effects ; Disease Models, Animal ; Dosage ; Dose-Response Relationship, Drug ; Drug dependence ; Estradiol - analogs & derivatives ; Estradiol - pharmacokinetics ; Estradiol - pharmacology ; Estrogen Antagonists - pharmacokinetics ; Estrogen Antagonists - pharmacology ; Ethinyl Estradiol - pharmacology ; Ethinylestradiol ; Female ; Fundamental and applied biological sciences. Psychology ; Hot Flashes - chemically induced ; Hot Flashes - metabolism ; Hypothalamus ; Hypothalamus - drug effects ; Mass spectrometry ; Mass spectroscopy ; Morphine ; Morphine - pharmacology ; Naloxone ; Naloxone - pharmacology ; Narcotic Antagonists - pharmacology ; Narcotics - pharmacology ; Ovariectomy ; Pretreatment ; Rats ; Rats, Sprague-Dawley ; Sex hormones ; Skin temperature ; Skin Temperature - drug effects ; Temperature dependence ; Uterus - drug effects ; Vertebrates: endocrinology ; Weight ; Xenoestrogens</subject><ispartof>Endocrinology (Philadelphia), 2008-10, Vol.149 (10), p.5219-5226</ispartof><rights>Copyright © 2008 by the Endocrine Society 2008</rights><rights>2008 INIST-CNRS</rights><rights>Copyright © 2008 by the Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c527t-fc6c1e8461a6c20781153a73ad658b1956d91a2df315637f26516a9bd030cbca3</citedby><cites>FETCH-LOGICAL-c527t-fc6c1e8461a6c20781153a73ad658b1956d91a2df315637f26516a9bd030cbca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20738544$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18599545$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Alfinito, Peter D</creatorcontrib><creatorcontrib>Chen, Xiaohong</creatorcontrib><creatorcontrib>Atherton, James</creatorcontrib><creatorcontrib>Cosmi, Scott</creatorcontrib><creatorcontrib>Deecher, Darlene C</creatorcontrib><title>ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functional Effects in the Brain after Systemic Dosing</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg·d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 α-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg·d) dose dependently inhibited this effect. ICI (3.0 mg/kg·d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg·d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg·d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions.</description><subject>17β-Estradiol</subject><subject>Animals</subject><subject>Antiestrogens</subject><subject>Biological and medical sciences</subject><subject>Blood-brain barrier</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Body temperature</subject><subject>Body weight</subject><subject>Body Weight - drug effects</subject><subject>Disease Models, Animal</subject><subject>Dosage</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug dependence</subject><subject>Estradiol - analogs & derivatives</subject><subject>Estradiol - pharmacokinetics</subject><subject>Estradiol - pharmacology</subject><subject>Estrogen Antagonists - pharmacokinetics</subject><subject>Estrogen Antagonists - pharmacology</subject><subject>Ethinyl Estradiol - pharmacology</subject><subject>Ethinylestradiol</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Hot Flashes - chemically induced</subject><subject>Hot Flashes - metabolism</subject><subject>Hypothalamus</subject><subject>Hypothalamus - drug effects</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Morphine</subject><subject>Morphine - pharmacology</subject><subject>Naloxone</subject><subject>Naloxone - pharmacology</subject><subject>Narcotic Antagonists - pharmacology</subject><subject>Narcotics - pharmacology</subject><subject>Ovariectomy</subject><subject>Pretreatment</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Sex hormones</subject><subject>Skin temperature</subject><subject>Skin Temperature - drug effects</subject><subject>Temperature dependence</subject><subject>Uterus - drug effects</subject><subject>Vertebrates: endocrinology</subject><subject>Weight</subject><subject>Xenoestrogens</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1v1DAQxS0EotvCjTOyhIBLU_wRO8kRti1dqRJIlHM064xpqqwTPM5h_3sSJVAJwcka6_dm5s1j7JUUF1JJ8QHDhRKizITR6gnbyCo3WSEL8ZRthJA6K5QqTtgp0cNU5nmun7MTWZqqMrnZsLjb7rgs1XlRCv4VA6YICYl_itAGDqHhN8ehT_fQwaF1_K4lGnH5B-LXY3Cp7QN0_Mp7dIn4pEr3-FvvE0b-7UgJZ_VlT2348YI989ARvlzfM_b9-upue5Pdfvm82368zZxRRcq8s05imVsJ1ilRlFIaDYWGxppyLytjm0qCaryWxurCK2ukhWrfCC3c3oE-Y--WvkPsf45IqT605LDrIGA_Um0rU8rK5hP45i_woR_jZIpqLbUw1XRTMVHnC-ViTxTR10NsDxCPtRT1nESNoZ6TqOckJvz12nTcH7B5hNfTT8DbFQBy0PkIwbX0h5sc69Lk83bvF64fh_-NzNaReiExNL2LbcAhItGjm38u-gtSzqrb</recordid><startdate>20081001</startdate><enddate>20081001</enddate><creator>Alfinito, Peter D</creator><creator>Chen, Xiaohong</creator><creator>Atherton, James</creator><creator>Cosmi, Scott</creator><creator>Deecher, Darlene C</creator><general>Endocrine Society</general><general>Oxford University Press</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20081001</creationdate><title>ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functional Effects in the Brain after Systemic Dosing</title><author>Alfinito, Peter D ; Chen, Xiaohong ; Atherton, James ; Cosmi, Scott ; Deecher, Darlene C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c527t-fc6c1e8461a6c20781153a73ad658b1956d91a2df315637f26516a9bd030cbca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>17β-Estradiol</topic><topic>Animals</topic><topic>Antiestrogens</topic><topic>Biological and medical sciences</topic><topic>Blood-brain barrier</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Body temperature</topic><topic>Body weight</topic><topic>Body Weight - drug effects</topic><topic>Disease Models, Animal</topic><topic>Dosage</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug dependence</topic><topic>Estradiol - analogs & derivatives</topic><topic>Estradiol - pharmacokinetics</topic><topic>Estradiol - pharmacology</topic><topic>Estrogen Antagonists - pharmacokinetics</topic><topic>Estrogen Antagonists - pharmacology</topic><topic>Ethinyl Estradiol - pharmacology</topic><topic>Ethinylestradiol</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Hot Flashes - chemically induced</topic><topic>Hot Flashes - metabolism</topic><topic>Hypothalamus</topic><topic>Hypothalamus - drug effects</topic><topic>Mass spectrometry</topic><topic>Mass spectroscopy</topic><topic>Morphine</topic><topic>Morphine - pharmacology</topic><topic>Naloxone</topic><topic>Naloxone - pharmacology</topic><topic>Narcotic Antagonists - pharmacology</topic><topic>Narcotics - pharmacology</topic><topic>Ovariectomy</topic><topic>Pretreatment</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Sex hormones</topic><topic>Skin temperature</topic><topic>Skin Temperature - drug effects</topic><topic>Temperature dependence</topic><topic>Uterus - drug effects</topic><topic>Vertebrates: endocrinology</topic><topic>Weight</topic><topic>Xenoestrogens</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Alfinito, Peter D</creatorcontrib><creatorcontrib>Chen, Xiaohong</creatorcontrib><creatorcontrib>Atherton, James</creatorcontrib><creatorcontrib>Cosmi, Scott</creatorcontrib><creatorcontrib>Deecher, Darlene C</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Endocrinology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alfinito, Peter D</au><au>Chen, Xiaohong</au><au>Atherton, James</au><au>Cosmi, Scott</au><au>Deecher, Darlene C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functional Effects in the Brain after Systemic Dosing</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2008-10-01</date><risdate>2008</risdate><volume>149</volume><issue>10</issue><spage>5219</spage><epage>5226</epage><pages>5219-5226</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><coden>ENDOAO</coden><abstract>Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg·d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 α-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg·d) dose dependently inhibited this effect. ICI (3.0 mg/kg·d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg·d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg·d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions.</abstract><cop>Bethesda, MD</cop><pub>Endocrine Society</pub><pmid>18599545</pmid><doi>10.1210/en.2008-0532</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | 17β-Estradiol Animals Antiestrogens Biological and medical sciences Blood-brain barrier Blood-Brain Barrier - metabolism Body temperature Body weight Body Weight - drug effects Disease Models, Animal Dosage Dose-Response Relationship, Drug Drug dependence Estradiol - analogs & derivatives Estradiol - pharmacokinetics Estradiol - pharmacology Estrogen Antagonists - pharmacokinetics Estrogen Antagonists - pharmacology Ethinyl Estradiol - pharmacology Ethinylestradiol Female Fundamental and applied biological sciences. Psychology Hot Flashes - chemically induced Hot Flashes - metabolism Hypothalamus Hypothalamus - drug effects Mass spectrometry Mass spectroscopy Morphine Morphine - pharmacology Naloxone Naloxone - pharmacology Narcotic Antagonists - pharmacology Narcotics - pharmacology Ovariectomy Pretreatment Rats Rats, Sprague-Dawley Sex hormones Skin temperature Skin Temperature - drug effects Temperature dependence Uterus - drug effects Vertebrates: endocrinology Weight Xenoestrogens |
| title | ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functional Effects in the Brain after Systemic Dosing |
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