Johns Hopkins brain scientists have hit on how and why some powerful drugs used for treating mental illnesses cause patients to gain so much weight that they often develop life-threatening complications such as diabetes and heart disease.
"We've now connected a whole class of antipsychotics to natural brain chemicals that trigger appetite," says Solomon H. Snyder, M.D., professor of neuroscience at the Johns Hopkins School of Medicine. "Our identification of the molecular players that link such drugs to increased food intake means there's now hope for finding a newer generation of drugs without the weight-gain side effects."
The discovery will be published online next week at the Proceedings of the National Academy of Sciences.
Previous research already had fingered increased levels and actions of one particular enzyme, AMPK, in brain cells as a control lever for appetite in mice and presumably humans.
Suspecting that antipsychotic drugs might spike AMPK in the brain to overact, the Johns Hopkins team injected mice with clozapine (Clozaril), which, with olanzapine (Zyprexa) and risperidone (Risperdal), is commonly prescribed for schizophrenia and bipolar disorder in people who do poorly on conventional drugs.
Mice given clozapine showed quadrupled AMPK activity compared to activity measured pre-drug.
The researchers then gave the mice leptin, a hormone that suppresses appetite, and as suspected, saw lowered AMPK levels.
Drilling down further into what controls AMPK and its boost of hunger, Sangwon Kim, Ph.D., a research associate and lead author of the study, "rounded up the usual suspects, brain proteins known to relay communication from cell to cell."
Systematically manipulating these cell-signaling proteins, Snyder's team found that blocking one in particular, a receptor site for histamine, a well-known player in triggering classic allergy symptoms, activates AMPK to the same extent as clozapine. To confirm that the histamine receptor connects the drug, AMPK activity and appetite, the team gave clozapine to mice genetically engineered without a histamine receptor.
Results? Peace. No heightened AMPK activity.
"Histamine also has a long history as a suspect in weight control, but no one ever could put a finger on the exact link," says Snyder. "The connection we've made between its receptor and appetite control is incredibly intriguing and opens new avenues for research on weight control, possibly including drugs that suppress appetite safely."
The research was funded by the U.S. Public Health Service, Canadian Institute of Health Research, National Institutes of Health and National Multiple Sclerosis Society.
Authors on the paper are Kim, Alex Huang, Adele Snowman and Snyder of Hopkins, and Cory Teuscher of the University of Vermont College of Medicine.
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