Researchers at the Lieber Institute for Brain Development (LIBD) believe they have solved a mystery that has been challenging scientists for more than 70 years: how the brain chemical dopamine is linked to schizophrenia, a devastating brain disorder often characterized by delusional thinking, hallucinations, and more. forms of psychosis.
By exploring the expression of genes in the caudate nucleus – an area of the brain associated with emotional decision-making – the researchers found physical evidence that neurons are unable to precisely control dopamine levels, and also identified the genetic mechanism that controls the flow of dopamine. Their findings are published today in the journal Nature Neuroscience.
So far, scientists have not been able to decipher whether dopamine binding is the causative factor or just a way to treat schizophrenia. We have the first evidence that dopamine is a causative agent of schizophrenia.”
Daniel R. Weinberger, MD, CEO and Director of the Lieber Institute and co-author of the study
Dopamine, a type of neurotransmitter, acts as a chemical messenger that sends signals between nerve cells — neurons in the brain — to change their activity and behavior. Dopamine is a reward neurotransmitter that enables people to feel happy.
According to the National Institute of Mental Health, schizophrenia is one of the 15 leading causes of disability worldwide, with psychotic symptoms such as hallucinations, delusions, and disturbed thinking, as well as decreased expression of feelings, decreased motivation to achieve goals, difficulty in social relationships, motor impairment, and cognitive impairment. Symptoms usually begin in late adolescence or early adulthood, although cognitive impairment and unusual behaviors sometimes appear in childhood. Current treatments for schizophrenia include antipsychotic medications that treat the symptoms of pyschosis, but not the cause.
“One of the major side effects of drugs used to treat schizophrenia is a lack of pleasure and joy,” said Dr. Jennifer Irwin, an investigator at the institute and one of the report’s authors. “In theory, if we could specifically target the dopamine receptor with drugs, this could be a new treatment strategy that wouldn’t limit patient happiness to the same extent.”
Scientists have known for decades that erratic levels of dopamine have something to do with psychosis and are a critical factor in schizophrenia, Alzheimer’s disease, and other neuropsychiatric disorders. Medications that increase dopamine in the brain, such as amphetamines, are known to cause psychosis. Medicines that treat psychosis do this by decreasing dopamine activity.
These observations have inspired generations of scientists to try to understand whether and how dopamine imbalances are actually linked to schizophrenia. Dopamine transmits information in the brain by interacting with proteins on the surface of brain cells, called dopamine receptors. By studying these receptors, scientists at the Lieber Institute have found new evidence that dopamine is a causative agent of schizophrenia.
Investigators examined hundreds of postmortem brain samples donated to the Lieber Institute from more than 350 people, some with schizophrenia and others without mental illnesses. They chose to focus on the caudate nucleus, a part of the brain critical to learning how to make complex thoughts and behaviors more automatic and intuitive, but also because it contains the brain’s richest supply of dopamine. They also studied a region of the human genome that large international genetic studies identified as being associated with risk of schizophrenia. This region contains dopamine-responsive protein receptor genes, suggesting the association of dopamine with schizophrenia. But while genetic data most suggest a role for dopamine receptors at risk for schizophrenia, the data are not conclusive and do not determine what the relationship actually is. Investigators at the Lieber Institute have gone further in discovering the mechanisms that make dopamine receptors a risk factor.
The mechanism is specifically located in a subtype of dopamine receptors, called the autoreceptor, which is located on the “male” side of the connection between neurons, the presynaptic terminal. This autoreceptor regulates the amount of dopamine that is released from the presynaptic neuron. If the autoreceptors are compromised, the flow of dopamine within the brain is poorly controlled, and too much dopamine is flowing for too long.
The researchers found that reduced expression of this autoreceptor in the brain explains the genetic evidence for disease risk. This is consistent with the prevailing hypothesis that too much dopamine plays a role in psychosis, and strong evidence that the mystery of dopamine and schizophrenia has finally been resolved.
Leading neuroscientist Dr. Saul Snyder praised the study as a breakthrough decades in the making. Dr. Snyder is Distinguished Service Professor of Neurology, Pharmacology, and Psychiatry and founder of the Department of Neuroscience at Johns Hopkins University School of Medicine, which bears his name. He was the scientist who discovered that antipsychotic drugs work by decreasing dopamine in the brain.
“There is a lot of confusing data indicating the importance of dopamine and dopamine receptors in schizophrenia,” said Dr. Snyder, who was not involved in this research project. “The main thing that these researchers have done is put the data together and convincingly demonstrate that dopamine systems are out of control in schizophrenia, and that this is a cause of disease.”
“For decades, people have debated the relationship of dopamine to schizophrenia,” Dr. Snyder said. They used to say, ‘Well, that’s interesting to speculate on, but there’s no solid evidence.’ But now that we have more rigorous data available, we keep coming back to the same story. You don’t have to call it a hypothesis anymore. ”
Lieber Institute for Brain Development
Benjamin, K.J.M., et al. (2022) Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and novel risk genes.. natural neuroscience. doi.org/10.1038/s41593-022-01182-7.