Developmental and regional changes in brain norepinephrine levels in diabetic C57BL/KsJ mice: effects of estradiol and progesterone.

Developmental and diabetes-associated changes in regional brain norepinephrine (NE) concentrations, and the influence of estradiol (E) and progesterone (P) on NE levels, were correlated with changes in blood glucose levels and body weight (obesity) in developing 4-16-week-old C57BL/KsJ (db/db) mice relative to corresponding age-matched control (+/?) parameters. Regional brain (i.e. amygdala, hypothalamus and medulla) NE levels were determined by high performance liquid chromatography. The (db/db) mice exhibited overt hyperglycemia and obesity relative to controls between 4 and 16 weeks of age. Hypothalamic NE levels in diabetics were chronically elevated as compared to those of age-matched controls by 8 weeks of age, and remained elevated through 16 weeks of age. Regional amygdaloid and medullary NE concentrations were comparable in (+/?) and (db/db) groups by 16 weeks. E-treatments normalized (db/db) hypothalamic NE concentrations to control levels between 8 and 16 weeks of age, but had no effect on amygdaloid or medullary values. In contrast, in 16 week old (db/db) mice, P-treatments elevated hypothalamic and medullary NE levels compared to controls and expected diabetic levels. These data demonstrate that a marked modification in regional brain NE concentrations occurs in association with the overt expression of the diabetes mutation during development in this species. Observed changes in adrenergic influences in specific CNS loci may be therapeutically modulated by ovarian steroid hormones, especially in the hypothalamic locus which is recognized to possess steroid-concentrating neurons. The observed normalization of regional brain NE concentrations by E-therapy may be causally related to the ovarian steroid-modulation of overt hyperglycemia and diabetes-associated neuronal degeneration in (db/db) mice.