Association of the antidiabetic effects of bromocriptine with a shift in the daily rhythm of monoamine metabolism within the suprachiasmatic nuclei of the Syrian hamster

Abstract

Bromocriptine, a dopamine D2 agonist, inhibits seasonal fattening and improves seasonal insulin resistance in Syrian hamsters. Alterations in daily rhythms of neuroendocrine activities are involved in the regulation of seasonal metabolic changes. Changes in circadian neuroendocrine activities that regulate metabolism are believed to be modulated by central circadian oscillators within the hypothalamic suprachiasmatic nuclei (SCN) of seasonal animals. We examined the association of metabolic responses to bromocriptine with its effects on the daily rhythms of metabolic hormones and daily monoamine profiles within the SCN, a primary circadian pacemaker known to regulate metabolism, in Syrian hamsters. Obese glucose-intolerant male Syrian hamsters (body weight [BW] 185 +/- 10 g) held on 14h daily photoperiods were treated at light onset with bromocriptine (800 microg/animal/day, ip) or vehicle for 2 weeks. Animals were then subjected to a glucose tolerance test (GTT) (3 g/kg BW, ip). Different subsets of animals (n = 6) from each treatment group were sacrificed at 0h/24h, 5h, 10h, 15h, or 20h after light onset for analyses of SCN monoamines, plasma insulin, prolactin, cortisol, thyroxin (T4), triiodothyronine (T3), glucose, and free fatty acids (FFAs). Compared with control values, bromocriptine treatment significantly reduced weight gain (14.9 vs. -2.9 g, p < .01) and the areas under the GTT glucose and insulin curves by 29% and 48%, respectively (p < .05). Basal plasma insulin concentration was markedly reduced throughout the day in bromocriptine-treated animals without influencing plasma glucose levels. Bromocriptine reduced the daily peak in FFA by 26% during the late light span (p < .05). Bromocriptine significantly shifted the daily plasma cortisol peak from the early dark to the light period of the day, reduced the plasma prolactin (mean 1.8 vs. 39.4 ng/dL) and T4 throughout the day (mean 1.6 vs. 3.8 microg/dL), and selectively reduced T3 during the dark period of the day (p < .01). Concurrently, bromocriptine treatment significantly reduced SCN dopamine turnover during the light period and shifted daily peaks of SCN serotonin and 5-hydroxy-indoleacetic acid (5-HIAA) content by 12h from the light to the dark period of the day (p < .05). This was confirmed by a further in vivo microdialysis study in which bromocriptine increased SCN extracellular 5-HIAA of glucose-intolerant hamsters during the dark phase (47% increase, p < .05) toward levels observed in normal glucose-tolerant hamsters. Thus, bromocriptine-induced resetting of daily patterns of SCN neurotransmitter metabolism is associated with the effects of bromocriptine on attenuation of the obese insulin-resistant and glucose-intolerant condition. A large body of corroborating evidence suggests that such bromocriptine-induced changes in SCN monoamine metabolism may be functional in its effects on metabolism.