New University of Pittsburgh research points to a potential approach to reducing the risk of diabetes associated with widely prescribed antipsychotic medications. The study, including experiments in mice, offers early evidence in support of co-administering antipsychotic medications that block dopamine (DA) D2-like receptors in the brain alongside drugs that stop antipsychotics from blocking those same receptors in the pancreas. For their tests the team developed a molecule, bromocriptine methiodide (BrMeI), that is structurally similar to bromocriptine—an FDA-approved treatment for type 2 diabetes—but which doesn’t easily cross the blood-brain barrier.

The researchers suggest their strategy could limit the metabolic side effects of antipsychotic drugs, including impaired control over blood sugar, or dysglycemia. “Antipsychotic medications don’t just stop working below the neck,” said senior author Zachary Freyberg, MD, PhD, associate professor of psychiatry and cell biology at Pitt’s School of Medicine. “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 team reported on its studies in Diabetes. In their paper, titled “Development of novel tools for dissection of central versus peripheral dopamine D2-like receptor signaling in dysglycemia,” the investigators concluded “Our results suggest the importance of coordinated, tandem signaling by both peripheral and CNS D2-like receptors for glycemic control, offers a new approach for studying metabolism, and potentially treating dysglycemia.”

Most prescription antipsychotic medications work by blocking the class of brain receptors that respond to the neurotransmitter dopamine—a cornerstone molecule of the brain’s reward system and brain-directed movement control. However, the D2 subtype of dopamine receptors that respond to antipsychotic medications are not exclusively found in the brain. “Discovery of D2-like receptors outside of the central nervous system (CNS) has expanded the scope of DA’s roles as a metabolic modulator,” the team wrote.

Zachary Freyberg, MD, PhD [UPMC]
Zachary Freyberg, MD, PhD [UPMC]
Freyberg’s earlier research showed that antipsychotic medications also block D2 receptors in the pancreas. The discovery highlighted that pancreatic dopamine plays a key role in controlling blood sugar by interacting with D2 receptors on the surface of pancreatic cells that control production and secretion of hormones insulin and glucagon. When the fragile balance between hormones that increase and decrease glucose is destabilized by antipsychotic medications, dysglycemia and diabetes may follow. But, as the authors noted, “It has been difficult to disentangle the respective metabolic contributions of CNS versus peripheral D2-like receptor signaling.”

The newly reported research indicates that peripheral dopamine signaling can be harnessed for therapeutic good. For their published study, carried out in collaboration with researchers at the National Institutes of Health’s National Institute on Drug Abuse (NIH NIDA), the team created a compound, bromocriptine methiodide, that can limit antipsychotic drugs from blocking D2 receptors in organs like the pancreas, but not those in the brain. “Here, we describe the first generation of new pharmacological tools intended to selectively target peripheral D2-like receptors,” the team continued. “Our aim was to employ peripherally limited drugs to examine the metabolic relevance of peripheral D2-like receptor signaling in dysglycemia and its treatment without the confounds of CNS actions.”

BrMeI is structurally similar to the FDA-approved type 2 diabetes drug bromocriptine but has a modification that makes it less likely to pass through the brain-blood barrier if administered systemically, so its activity is limited to the periphery.

The team’s early studies in mice suggested that dopamine’s effects on glucose metabolism require communication between the brain and the peripheral organs including the pancreas. Experiments showed that, unlike systemically administered bromocriptine that improves the glucose profile of insulin-resistant mice, peripherally limited BrMeI, or bromocriptine delivered directly to the brain, failed to show improvements. “Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo,” the investigators reported. “In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI.”

Drugs such as BrMeI that can stop antipsychotic medications from acting on peripheral targets may therefore be useful in preventing, or even reversing, dysglycemia. “Our results suggest that coordinated signaling via CNS and peripheral D2-like receptors is required for bromocriptine’s metabolic effects, underscoring the importance of both peripheral and CNS dopaminergic metabolic regulation,” the team stated. “Moreover, the design of peripherally-limited dopaminergic agonists opens the door to new classes of drugs for more effective treatment of dysglycemia.”

Freyberg and collaborators at Pitt are in the early stages of a safety clinical trial to ensure that the therapeutic effects of antipsychotic drugs are preserved when administered in tandem with the already FDA-approved bromocriptine. It’s hoped that a larger trial may in future be launched to test the efficacy of BrMeI and similar molecules for limiting dysglycemia.

“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 Freyberg. “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,” the investigators further stated.

Freyberg continued, “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.”

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