University of Wisconsin School of Medicine and Public Health researchers report that amylin, which is secreted by the pancreas and which penetrates into the brain, helps rats with schizophrenia-like symptoms. The surprising finding was the result of collaborative research by Dr. Brian Baldo, who studies addiction, food reward, and satiation in the brain, and his wife, Dr. Vaishali Bakshi, who studies schizophrenia and other mental illnesses. They met as undergraduates at Harvard two decades ago, but this paper is the first research collaboration for the couple.
What brought them together in this collaboration was Baldo’s longstanding interest in the amylin system, because early reports indicated an unusually high concentration of amylin binding in a brain structure called the nucleus accumbens. As an expert on this brain-reward site, Baldo is interested in amylin’s action on motivation, impulsivity, and food reward. Several years ago, when he published the first work showing that amylin acts in the nucleus accumbens to curtail feeding responses, he suspected that amylin may have far-ranging effects on several accumbens-based behaviors. Bakshi was interested in the brain region because it acts like a gatekeeper, helping to filter out unimportant stimulation from the brain.
“If the gating doesn’t work, too much information comes flooding in and that is what is thought to be one of the primary problems in schizophrenia,” says Bakshi. “It becomes difficult to separate the signal from the noise, and perhaps to tell reality from hallucinations.”
Also, many of the ‘second-generation’ antipsychotic drugs for schizophrenia (such as clozapine), although highly effective at treating psychosis symptoms, have the side effect of promoting obesity and metabolic disorders. This increases morbidity and reduces treatment compliance. Thus, finding new treatments that do not carry these risks is a top priority in mental-health research.
In a series of experiments with graduate student Sarah Baisley and senior research specialist Quentin Bremer, the team examined the effects of infusing synthetic amylin into the brains of rats with psychosis-like symptoms. They measured effectiveness by tracking prepulse inhibition (PPI), a measure of how well the brain filters unimportant stimuli; the higher the PPI, the better the filtering. Using a well-established experimental model of schizophrenia-like symptoms, they gave the stimulant amphetamine, which reliably disrupts PPI, modeling psychosis-like symptoms seen in human amphetamine abusers. They found that stimulating accumbens amylin systems strongly reversed amphetamine’s disruptive effect, restoring normal levels of PPI; PPI improvements are a well-known feature of clinically effective antipsychotic medications.
In a second experiment, they tried the opposite manipulation: instead of stimulating amylin systems, they blocked amylin receptors with an antagonist drug (but gave no amphetamine). This amylin blockade had the startling effect of actually causing a psychosis-like PPI disruption, indicating that naturally occurring amylin arriving in the accumbens helps maintain normal information filtering.
The amylin action was limited to the ventral region of the nucleus accumbens, which the investigators found to be laden with gene expression for amylin receptors, and had no effect in the dorsal region, where no amylin receptor genes were present. This is important because first-generation schizophrenia drugs, such as haloperidol (Haldol), also affected dopamine in the dorsal region and produced Parkinson’s-like side effects such as impaired walking (tardive dyskinesia). Thu, amylin-based compounds could provide benefits by selectively targeting the ‘problem areas’ of the brain while leaving untouched the other sites from which harmful side effects emerge.
Baldo says that synthetic amylin, known as Symlin, is already FDA-approved for the treatment of diabetes. Hence, the drug could possibly be used as an adjunct treatment to prevent the weight gain that current antipsychotics promote, while at the same time reducing psychosis symptoms and lowering the needed antipsychotic dose.
“This is exciting because it is a great example of how the brain’s chemical anatomy led us to a potential new treatment for mental illness. There is a great need for new antipsychotics, and a great need to reduce weight-gain side effects, and there the amylin receptors were — exactly in the right place,” says Baldo.
Bakshi noted that most historical drugs for serious mental illness were discovered by accident. Thorazine, for example, was created as an anesthesia drug.
“They were discovered serendipitously to affect mental illness, and then reverse-engineered to learn what their mechanism of action in the brain was,” she said. “This amylin study is one of the few examples to go in the other direction, looking at brain architecture to find what might be effective and then test the clinical utility of the target.”
University of Wisconsin School of Medicine and Public Health