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

Bromocriptine, a dopamine D-2 agonist, inhibits seasonal fattening and impr oves seasonal insulin resistance in Syrian hamsters. Alterations in daily r hythms of neuroendocrine activities are involved in the regulation of seaso nal metabolic changes. Changes in circadian neuroendocrine activities that regulate metabolism are believed to be modulated by central circadian oscil lators within the hypothalamic suprachiasmatic nuclei (SCN) of seasonal ani mals. We examined the association of metabolic responses to bromocriptine w ith its effects on the daily rhythms of metabolic hormones and daily monoam ine profiles within the SCN, a primary circadian pacemaker known to regulat e metabolism, in Syrian hamsters. Obese glucose-intolerant male Syrian hams ters (body weight [BW] 185 +/- 10 g) held on 14h daily photoperiods were tr eated at light onset with bromocriptine (800 mu g/animal/day, ip) or vehicl e 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 fo r analyses of SCN monoamines, plasma insulin, prolactin, cortisol, thyroxin (T-4), triiodothyronine (T-3), glucose, and free fatty acids (FFAs). Compa red with control values, bromocriptine treatment significantly reduced weig ht 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-tre ated animals without influencing plasma glucose levels. Bromocriptine reduc ed the daily peak in FFA by 26% during the late light span (p < .05). Bromo criptine significantly shifted the daily plasma cortisol peak from the earl y dark to the light period of the day, reduced the plasma prolactin (mean 1 .8 vs. 39.4 ng/dL) and T-4 throughout the day (mean 1.6 vs. 3.8 mu g/dL), a nd selectively reduced T-3 during the dark period of the day (p < .01). Con currently, bromocriptine treatment significantly reduced SCN dopamine turno ver 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 dar k period of the day (p < .05). This was confirmed by a further in vivo micr odialysis study in which bromocriptine increased SCN extracellular 5-HIAA o f glucose-intolerant hamsters during the dark phase (47% increase, p < .05) toward levels observed in normal glucose-tolerant hamsters. Thus, bromocri ptine-induced resetting of daily patterns of SCN neurotransmitter metabolis m is associated with the effects of bromocriptine on attenuation of the obe se insulin-resistant and glucose-intolerant condition. A large body of corr oborating evidence suggests that such bromocriptine-induced changes in SCN monoamine metabolism may be functional in its effects on metabolism.