title: Increased responsiveness of ventromedial hypothalamic neurons to norepinephrine in obese versus lean mice: relation to the metabolic syndrome.
abstract: Studies of the effects of acute and chronic norepinephrine (NE) infusion into the ventromedial hypothalamus (VMH) of rodents indicate important roles for VMH NE activities in the development of the obese-glucose intolerant state. Moreover, elevated endogenous levels of NE and/or its metabolites have been observed in a variety of obese-glucose intolerant animal models. We therefore investigated the VMH neuronal electrophysiologic responsiveness to iontophoretically applied NE in lean-euglycemic and obese-hyperglycemic mice. Additionally, the effect of dopamine agonist treatment (which reduces obesity and hyperglycemia) on VMH responsiveness to NE was examined in obese-hyperglycemic mice. Obese (ob/ob) mice were treated daily for 14 days with either bromocriptine (BC, D2 agonist) (10 mg/kg) plus SKF38393 (SKF, D1 agonist) (20 mg/kg) or vehicle. Lean mice were also similarly treated with vehicle. Twenty-seven hours following the final treatment, mice were anesthetized to obtain electrophysiologic responses of glutamate activated VMH neurons to local NE administration. In all three study groups, NE administration inhibited glutamate evoked neuronal activity in the majority (90%) of recorded neurons. No response to NE was observed in the remaining 10% of neurons. Also within all three groups there existed two patterns of response to NE; a) long duration (>2 min) and low threshold (<20 nA) and b) short duration and high threshold. Relative to lean mice, obese mice exhibited a significant 70% increase in average duration of response, 3-fold increase in percent neurons with long duration of response, and 2-fold increase in percent neurons with low threshold of response. BC/SKF treatment of obese mice significantly reduced the percent VMH neurons with long duration and low threshold of response to NE to resemble the VMH neuronal responsiveness to NE observed in lean mice. Increased VMH responsiveness to NE is part of the endogenous neurophysiology of obese-hyperglycemic ob/ob mice. Taken together with previous findings mentioned above, the present results suggest that this increased VMH responsiveness to NE contributes to the pathophysiology of the obese-hyperglycemic state.
authors.affiliation: Ergo Science Corp., N. Andover, MA 01845, USA.
authors.forename: K Z
authors.initials: KZ
authors.lastname: Kraszewski
authors.forename: A H
authors.initials: AH
authors.lastname: Cincotta
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D004594:Electrophysiology; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D006943:Hyperglycemia / Q000503:physiopathology* / Q000517:prevention & control; D007478:Iontophoresis; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology*; D009765:Obesity / Q000503:physiopathology* / Q000517:prevention & control; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D013577:Syndrome; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects* / Q000503:physiopathology*
chemical_list: D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D001971:Bromocriptine; D018698:Glutamic Acid; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D009638:Norepinephrine