Short term, circadian-timed dopamine precursor (L-DOPA) therapy can produce long term advances or delays in the annual cycle of metabolism in several seasonal vertebrate species as function of the time of day of its administration. It has also been demonstrated that dopamine D1 plus D2 receptor agonist (DA) therapy improves dysmetabolism in leptin inactive animal models of metabolic syndrome to a level that cannot be achieved with either agonist alone. This study therefore investigated the potential for short term DA therapy to induce long term reduction in hyperglycemia in ob/ob mice. In two separate studies, animals were treated either with the dopamine D1 plus D2 agonists (SKF38393 and bromocriptine, respectively) (each 10 mg/kg BW ip) or vehicle prior to the onset of waking for 14 days. After 7 and 11 days of treatment, DA markedly reduced plasma hyperglycemia, triglyceride and FFA levels, and elevated corticosterone levels (Study 1). Remarkably, these DA effects remained 28 days after cessation of the therapy. In Study 2, conducted to assess DA effects on impaired glucose intolerance (IGT), DA therapy again produced long-lasting improvements in hyperglycemia and IGT (Table). This study demonstrates a long-lasting amelioration of dysglycemia in ob/ob mice with a systemic therapy. These studies provide a basis for contemplating development of a clinical DA therapy for metabolic disease.

S. Luo: Employee; Self; VeroScience LLC. M. Ezrokhi: Employee; Self; VeroScience LLC. N. Cominos: Employee; Self; VeroScience LLC. B. Raiche: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC.

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