Researchers from the University of Pittsburgh recently published findings that suggest using the peripheral action of bromocriptine, a dopamine agonist with limited penetration through the blood-brain barrier, to offset drug-induced metabolic side effects may pave the way for the development of a first generation of drugs designed to selectively target peripheral dopamine signaling and of novel strategies to treat abnormal blood glucose.

Zachary Freyberg, MD, PhD, associate professor of psychiatry and cell biology at the University of Pittsburgh and senior author of the study and colleagues explored the potential metabolic contributions of dopamine (DA) D2-like receptors, found in the central nervous system (CNS) and peripheral tissues. The work builds on established research that informs of disruptions in D2-like receptor signaling associated with “dysglycemia.” These D2-like receptors include both D2 and D3 receptors, and although potential influence is known to exist, the type and magnitude of their influence is not well known.

The team selected bromocriptine methiodide as their agent of choice, with pharmacologic action in the periphery with limited penetration through the blood-brain barrier and its recognized value in glucose control with an FDA-approved indication for the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise. Bromocriptine administration is reported to reduce postprandial plasma glucose levels due to enhanced suppression of hepatic glucose production and plasma-free fatty acid and triglyceride levels. Bromocriptine has not been shown to enhance insulin secretion or insulin sensitivity in peripheral muscle tissues, however.

With dopamine antagonist antipsychotic–associated metabolic symptoms representing a significant medical challenge in the treatment of mental health, the researchers connected the dots. “Antipsychotic medications don’t just stop working below the neck,” said Dr. Freyberg, adding, “Maintaining glucose metabolism requires the brain to be in constant communication with the rest of the body, and vice versa. Next-generation antipsychotic drugs can be modified as a new strategy to control dysglycemia and diabetes.

“The fact that both the brain and the body are required to maintain stable glycemic control provides a novel dimension in understanding neuropsychiatry and begins to integrate disparate pieces of knowledge about different organ systems into a coherent whole,” said Dr. Freyberg.

“The majority of psychiatric medications are prescribed by general practitioners and not psychiatrists,” he added. “We hope that our research builds awareness about the importance of communication between the brain and the rest of the body in maintaining physiological functions and reminds clinicians that they should also consider that drugs designed to act on targets in the brain, like psychiatric medications, may also have significant actions outside of the brain when making prescription recommendations.”

The authors concluded, “Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.”

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