{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:36:27Z","timestamp":1787765787441,"version":"build-2784847793"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2012,9,6]],"date-time":"2012-09-06T00:00:00Z","timestamp":1346889600000},"content-version":"vor","delay-in-days":1285,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Obesity"],"published-print":{"date-parts":[[2009,3]]},"abstract":"<jats:p>The noradrenaline (NA) and serotonin reuptake inhibitor, sibutramine, gives effective weight loss, but full efficacy cannot be attained at approved doses due to cardiovascular side effects. We assessed in rats the contributions of NA and serotonin transporters to sibutramine's hypophagic and cardiovascular effects, and whether selective 5\u2010hydroxytryptamine (5\u2010HT<jats:sub>1A<\/jats:sub>) receptor activation could counteract the latter without affecting the former. Food intake was assessed in freely feeding rats and cardiovascular parameters in conscious telemetered rats.<jats:italic>Ex vivo<\/jats:italic>radioligand binding was used to estimate brain monoamine transporter occupancy. Sibutramine (1\u201310 mg\/kg p.o.) dose\u2010dependently reduced food intake; however, 10 mg\/kg p.o. markedly elevated blood pressure and heart rate. Sibutramine gave greater occupancy of NA than serotonin reuptake sites. Coadministration of the selective 5\u2010HT<jats:sub>1A<\/jats:sub>agonist F\u201011440 (2.5 mg\/kg p.o.) attenuated sibutramine\u2010induced hypertension and tachycardia without altering its food intake effects. The selective NA reuptake inhibitors, nisoxetine or reboxetine, did not alter food intake alone, but each reduced food intake when combined with F\u201011440. These results suggest that sibutramine\u2010induced hypophagic and cardiovascular effects are largely due to increased brain synaptic NA via NA reuptake inhibition, and that 5\u2010HT<jats:sub>1A<\/jats:sub>activation can counter the undesirable cardiovascular effects resulting from increased sympathetic activity. Selective NA reuptake inhibitors did not reduce food intake alone but did when combined with 5\u2010HT<jats:sub>1A<\/jats:sub>activation. Hence increased synaptic serotonin, via serotonin reuptake inhibition or 5\u2010HT<jats:sub>1A<\/jats:sub>activation, together with increased NA, would appear to produce hypophagia. Thus weight loss with minimal cardiovascular risk could be achieved by 5\u2010HT<jats:sub>1A<\/jats:sub>activation combined with NA transporter blockade.<\/jats:p>","DOI":"10.1038\/oby.2008.550","type":"journal-article","created":{"date-parts":[[2009,1,19]],"date-time":"2009-01-19T15:55:40Z","timestamp":1232380540000},"page":"467-473","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["5\u2010HT<sub>1A<\/sub>Activation Counteracts Cardiovascular But Not Hypophagic Effects of Sibutramine in Rats"],"prefix":"10.1002","volume":"17","author":[{"given":"Gerard H.","family":"Thomas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Babbs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary E.","family":"Chatfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Kr\u00fclle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Widdowson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Provost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James G.","family":"McCormack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,9,6]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1037\/0022-006X.65.1.79"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0288"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/oby.2004.251"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0680124"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.282.16.1523"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1550-8528.1996.tb00544.x"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(98)00411-2"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijo.0802216"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/oby.2003.152"},{"key":"e_1_2_7_11_2","first-page":"345","article-title":"A pilot study to evaluate the pharmacokinetics of sibutramine in healthy subjects under fasting and fed conditions","volume":"7","author":"Abolfathi Z","year":"2004","journal-title":"J Pharm Pharmaceut Sci"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.164.9.994"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2005.00481.x"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1988.tb05303.x"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.061259"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.02.002"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(89)90048-8"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02244604"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(93)90181-2"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(95)00134-4"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0701311"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0701312"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199001001-00010"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0361-9230(01)00612-8"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000169970.68151.17"},{"key":"e_1_2_7_26_2","unstructured":"HealDJ CheethamSC.Therapeutic agents.2001;WO 01\/62341."},{"key":"e_1_2_7_27_2","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/S0022-3565(24)37788-2","article-title":"F 11440, a potent, selective, high efficacy 5\u2010HT1A receptor agonist with marked anxiolytic and antidepressant potential","volume":"287","author":"Koek W","year":"1998","journal-title":"J Pharmacol Exp Therap"},{"key":"e_1_2_7_28_2","unstructured":"WiddowsonPS BabbsAJ CheethamSCet al.Prevention of hypertension and tachycardia in rats treated with the anti\u2010obesity agent sibutramine by co\u2010administration with the 5\u2010HT1Aagonist F\u201011440 No. 62.5\u00d76 Neuroscience Atlanta 2006; 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