Researchers are unraveling how the brain chemical dopamine is linked to schizophrenia

Researchers are unraveling how the brain chemical dopamine is linked to schizophrenia

Researchers at the Lieber Institute for Brain Development (LIBD) believe they have solved a mystery that has challenged scientists for more than 70 years: how the brain chemical dopamine is linked to schizophrenia, the often devastating brain disorder characterized by delusional thinking, hallucinations and other forms of psychosis.

By studying the expression of genes in the caudate nucleus - a region of the brain associated with emotional decision-making - the researchers found physical evidence that neuronal cells are unable to precisely control dopamine levels, and they also identified the genetic mechanism that controls dopamine flow. Their results were published today in the journal Nature Neuroscience.

Until now, scientists have not been able to decipher whether the dopamine connection was a causative factor or just a way to treat schizophrenia. We have the first evidence that dopamine is a causative factor in schizophrenia.”

Daniel R. Weinberger, MD, executive director 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 neurons - nerve cells in the brain - to change their activity and behavior. Dopamine is the reward neurotransmitter that allows people to feel pleasure.

According to the National Institute of Mental Health, schizophrenia is one of the 15 most common causes of disability worldwide, with psychotic symptoms such as hallucinations, delusions and thought disorders, as well as reduced expression of emotions, reduced motivation to achieve goals, difficulties in social relationships, motor impairment and cognitive impairment. Symptoms typically begin in late adolescence or early adulthood, although cognitive impairment and unusual behaviors sometimes appear in childhood. Current treatments for schizophrenia include antipsychotics, which treat the symptoms of psychosis but not the cause.

“One of the main side effects of the medications used to treat schizophrenia is the lack of pleasure and pleasure,” said Dr. Jennifer Erwin, a researcher at the institute and one of the report's authors. “If we could target the dopamine receptor specifically with medication, that could theoretically be a new treatment strategy that wouldn’t limit a patient’s happiness so much.”

Scientists have known for decades that irregular dopamine levels have some connection with psychosis and are a critical factor in schizophrenia, Alzheimer's disease and other neuropsychiatric disorders. Drugs that increase dopamine in the brain, such as amphetamines, are known to cause psychosis. Medications that treat psychosis do so by reducing dopamine activity.

These observations have inspired generations of scientists to try to understand whether – and how – an imbalance of dopamine is 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 confirming that dopamine is a causative factor in schizophrenia.

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Investigators examined hundreds of brain samples donated to the Lieber Institute from over 350 people, some with schizophrenia and others without psychiatric illness. They chose to focus on the caudate nucleus, a part of the brain that is crucial for learning how to make complex ideas and behaviors more automatic and intuitive, but also because it has the brain's richest supply of dopamine. They also examined a region of the human genome that has been linked to the risk of schizophrenia in large international genetic studies. This region contains the genes for the protein receptors that respond to dopamine, suggesting the dopamine-schizophrenia connection. But while genetic data suggests at most a role for dopamine receptors at risk for schizophrenia, the data is inconclusive and does not identify what the relationship actually is. The researchers at the Lieber Institute took a critical approach to discovering the mechanisms that make dopamine receptors a risk factor.

The mechanism exists specifically in a subtype of dopamine receptor called the autoreceptor, which lies on the “male” side of the connection between neurons, the presynaptic terminal. This autoreceptor regulates how much dopamine is released from the presynaptic neuron. When the autoreceptors are impaired, the flow of dopamine in the brain is poorly controlled and too much dopamine flows for too long.

The researchers found that reduced expression of this autoreceptor in the brain explains the genetic evidence of disease risk. This is consistent with the prevailing hypothesis that too much dopamine plays a role in psychosis and is strong evidence that the dopamine-schizophrenia puzzle has finally been solved.

Groundbreaking neuroscientist Dr. Sol Snyder hailed the study as a breakthrough decades in the making. Dr. Snyder is a distinguished professor of neuroscience, pharmacology and psychiatry and founder of the Department of Neuroscience at the Johns Hopkins University School of Medicine that bears his name. He was the scientist who discovered that antipsychotics work by reducing brain dopamine.

“There is a lot of confusing data suggesting the relevance of dopamine and dopamine receptors in schizophrenia,” said Dr. Snyder, who was not involved in this research project. “The most important thing these researchers have done is collect data that ties everything together and shows in a convincing way that the dopamine system is out of whack in schizophrenia and that this is causal to the disease.”

“The connection between dopamine and schizophrenia has been discussed for decades,” said Dr. Snyder. "They used to say, 'Well, it's interesting to speculate about it, but there's no solid evidence.' But now that we have much more precise data, we keep coming back to the same story. You don't have to call it a hypothesis anymore."

Source:

Dear Institute for Brain Development

Reference:

Benjamin, KJM, et al. (2022) Analysis of the transcriptome of the caudate nucleus in individuals with schizophrenia highlights the effect of antipsychotics and novel risk genes. Nature neuroscience. doi.org/10.1038/s41593-022-01182-7.

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