Neuroendocrine mechanisms of behavioral changes induced by hypoglycemia

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Nutritional Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2010

Author dc:creator

• Park, Min Jung

Contributors dc:contributor

• Freund, Gregory G.
• Donovan, Sharon M.
• Johnson, Rodney W.
• Woods, Jeffrey A.

• insulin
• hypoglycemia
• social exploration
• social withdrawal
• depression
• depressive-like behavior
• adrenergic receptors
• antidepressants
• norepinephrine
• epinephrine
• corticosterone
• mice

Statement dc:rights

• Copyright 2010 Min Jung Park

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/17052

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/17052