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Freund, Gregory G. Donovan, Sharon M. Freund, Gregory G. Johnson, Rodney W. Woods, Jeffrey A. Park, Min Jung 2010-08-31T20:30:38Z 2010-08-31T20:30:38Z 2012-09-07T16:43:39Z 2010-08-31T20:30:38Z 2010-08 Hypoglycemia is associated with a variety of adverse behaviors including fatigue, confusion, social withdrawal, anhedonia and depressive-like behaviors. While these clinical symptoms are well characterized, the mechanisms of their cause are not understood. Here, we investigated how insulin-induced hypoglycemia causes social withdrawal and changes in mood. To investigate effects on social withdrawal, male 8-12-week-old C57BL/6J mice were injected intraperitoneally with saline and/or insulin (0.8 or 1.2units/kg). Insulin generated significant hypoglycemia with the lowest blood glucose levels of 64±4 and 48±5mg/dl for 0.8 and 1.2units/kg of insulin, respectively. Insulin at either dose caused near total social withdrawal at 0.75h, with full recovery not occurring until 4h (0.8units/kg) or 8h (1.2units/kg) post-insulin injection. Insulin also caused a marked elevation in plasma catecholamines. Basal 12h fasting norepinephrine (NE) and epinephrine (Epi) were 287±38 and 350±47pg/ml, respectively. Insulin at 0.8units/kg increased plasma NE and Epi to 994±73 and 1842±472 pg/ml, respectively. Administration of exogenous NE or Epi caused social withdrawal similar in magnitude to insulin. Importantly, administration of the β-2 adrenergic receptor agonist terbutaline also caused social withdrawal, while administration of the β-2 adrenergic receptor antagonist butoxamine blocked NE-induced social withdrawal. Finally, butoxamine blocked insulin-induced social withdrawal. These data demonstrate that hypoglycemia-associated social withdrawal is dependent on catecholamines via a β-2 receptor-mediated pathway. Next, we investigated how insulin-induced hypoglycemia causes anhedonia and depressive-like behavior. Saccharin preference testing 24h post hypoglycemia showed that mice receiving insulin (0.8 units/kg) had saccharin aversion (62% vs 90.5% of total fluid consumption). In addition, mice administered insulin had increased immobility in the forced swim test that took 48h to rectify. Insulin at 0.8units/kg increased plasma corticosterone (325±23pg/ml vs. 119±32pg/ml), Epi (814±254pg/ml vs. 350±40pg/ml), and NE (541±155pg/ml vs. 265±28pg/ml) at 24h post insulin treatment. Importantly, blocking of the adrenergic receptors with phentolamine, metoprolol and butoxamine, or treatment with the anti-depressants (fluoxetine and desipramine) ablated the insulin-induced saccharin aversion and increased immobility in forced swim test. Taken together, these data indicate that anhedonia and depressive-like behaviors are induced by hypoglycemia and those behaviors are dependent on catecholamines in an adrenergic receptor-mediated manner. Item withdrawn by Alexis Thompson (athmpsn1@illinois.edu) on 2010-07-15T13:52:58Z Item was in collections: University of Illinois Theses & Dissertations (ID: 1) No. of bitstreams: 2 Park_Min Jung.doc: 1629696 bytes, checksum: 8ac8aef2ca91dcaf7d0af8016ffac6fa (MD5) Park_Min Jung.pdf: 1157274 bytes, checksum: 3b54ce5e9646296dfc6900574e37cbdf (MD5) Made available in DSpace on 2010-08-31T20:30:38Z (GMT). No. of bitstreams: 4 Park_Min Jung.pdf: 1157274 bytes, checksum: 3b54ce5e9646296dfc6900574e37cbdf (MD5) Park_Min Jung.doc: 1629696 bytes, checksum: 8ac8aef2ca91dcaf7d0af8016ffac6fa (MD5) Park_Min_Jung.pdf: 1155863 bytes, checksum: 96f5f8fb5ff7c7fbb21768464464d247 (MD5) license.txt: 4057 bytes, checksum: 85e36682cffae20cc36b3f85f044d7ed (MD5) Item marked as restricted to the 'Administrator' Group (id=1) by William Ingram (wingram2@illinois.edu) on 2010-08-31T20:32:55Z Item is restricted until 2012-08-31T20:32:49Z Item reinstated by Sarah Shreeves (sshreeve@illinois.edu) on 2012-09-07T16:43:39Z Item was in collections: University of Illinois Dissertations and Theses (ID: 204) Dissertations and Theses - Nutritional Sciences (ID: 680) No. of bitstreams: 5 Park_Min Jung.pdf: 1157274 bytes, checksum: 3b54ce5e9646296dfc6900574e37cbdf (MD5) Park_Min Jung.doc: 1629696 bytes, checksum: 8ac8aef2ca91dcaf7d0af8016ffac6fa (MD5) Park_Min_Jung.pdf: 1155863 bytes, checksum: 96f5f8fb5ff7c7fbb21768464464d247 (MD5) license.txt: 4057 bytes, checksum: 85e36682cffae20cc36b3f85f044d7ed (MD5) Park_Min_Jung.pdf.txt: 170588 bytes, checksum: d712f7278843a9c1c356e08c2d1f491b (MD5) Item released from any restrictions by Sarah Shreeves (sshreeve@illinois.edu) on 2012-09-07T16:43:39Z http://hdl.handle.net/2142/17052 en Copyright 2010 Min Jung Park insulin hypoglycemia social exploration social withdrawal depression depressive-like behavior adrenergic receptors antidepressants norepinephrine epinephrine corticosterone mice Neuroendocrine mechanisms of behavioral changes induced by hypoglycemia Nutritional Sciences 1971 Nutritional Sciences 0191 University of Illinois at Urbana-Champaign Dissertation Ph.D. PHD:Nutritional Sciences -UIUC 10KS0191PHD