How does the brain chemical dopamine relate to schizophrenia? It is a question that vexed scientists for more than 70 years, and now researchers at the Lieber Institute for Brain Development (LIBD) believe they have solved the challenging riddle. This new understanding may lead to better treatment of schizophrenia, an often-devastating brain disorder characterized by delusional thinking, hallucinations, and other forms of psychosis. Through their exploration of the expression of genes in the caudate nucleus – a region of the brain linked to emotional decision-making – the scientists uncovered physical evidence that neuronal cells are unable to precisely control levels of dopamine. They also identified the genetic mechanism that controls dopamine flow. Their findings were published today (November 1) in the journal Nature Neuroscience. “Until now, scientists have been unable to decipher whether the dopamine link was a causative factor or solely a way to treat schizophrenia,” said Daniel R. Weinberger, M.D., a co-author of the study. “We have the first evidence that dopamine is a causative factor in schizophrenia.” Weinberger is chief executive and director of the Lieber Institute. 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 enables people to feel pleasure. According to the National Institute of Mental Health, schizophrenia is 1 of the top 15 leading causes of disability worldwide. People with the affliction suffer from psychotic symptoms such as hallucinations, delusions, and disordered thinking, as well as reduced expression of emotions, reduced motivation to accomplish goals, difficulty 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 antipsychotic drugs which address the symptoms of pyschosis, but not the cause. “One of the major side effects of the drugs used to treat schizophrenia is lack of pleasure and joy,” said Dr. Jennifer Erwin, an investigator at the Institute and one of the authors on the report. “In theory, if we could target the dopamine receptor specifically with drugs, that could be a new strategy for treatment that would not limit a patient’s joy as much.” Scientists have known for decades that irregular levels of dopamine have some connection to 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. Drugs 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 actually relates to schizophrenia. Dopamine transmits information in the brain by interacting with proteins on the surface of brain cells, called dopamine receptors. By studying those receptors, scientists at the Lieber Institute have come up with novel evidence confirming that dopamine is a causative factor for schizophrenia. The investigators examined hundreds of post-mortem specimen brains donated to the Lieber Institute from over 350 individuals, some with schizophrenia and others without psychiatric illness. They chose to focus on the caudate nucleus, a part of the brain that is critically important 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 studied a region of the human genome that large international genetic studies have identified as being connected with the risk of schizophrenia. This region contains the genes for the protein receptors that respond to dopamine, which points to the dopamine-schizophrenia connection. But while genetic data suggest at most a role of dopamine receptors at risk for schizophrenia, the data are not conclusive and do not identify what the relationship actually is. The investigators at the Lieber Institute went critically further in discovering the mechanisms that make dopamine receptors a risk factor. The mechanism exists specifically in a subtype of the 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. If autoreceptors are compromised, the flow of dopamine within the brain is poorly controlled, and too much dopamine flows for too long. The investigators found that decreased expression of this autoreceptor in the brain explains the genetic evidence of risk for illness. This is consistent with the prevailing hypothesis that too much dopamine plays a role in psychosis, and strong evidence that the dopamine-schizophrenia riddle has at last been solved. The pioneering neuroscientist Dr. Sol Snyder hailed the study as a breakthrough many decades in the making. Dr. Snyder is a distinguished service professor of neuroscience, pharmacology, and psychiatry and founder of the Department of Neuroscience at the Johns Hopkins University School of Medicine, which bears his name. He was the scientist who discovered that antipsychotic drugs work by reducing brain dopamine. “There’s lots of muddled data indicating the relevance of dopamine and dopamine receptors in schizophrenia,” said Dr. Snyder, who was not involved in this research project. “The key thing these researchers have done is to collect data that puts it all together and in a fashion that is persuasive in establishing that dopamine systems are out of kilter in schizophrenia, and that is causal to the disease.” “For decades, people have debated the dopamine connection to schizophrenia,” Dr. Snyder said. “They used to say, ‘Well, this is interesting to speculate about, but there’s no solid evidence.’ But now that we have much more rigorous data available, we keep coming back to the same story. You don’t have to call it a hypothesis anymore.” Reference: “Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes” by Kynon J. M. Benjamin, Qiang Chen, Andrew E. Jaffe, Joshua M. Stolz, Leonardo Collado-Torres, Louise A. Huuki-Myers, Emily E. Burke, Ria Arora, Arthur S. Feltrin, André Rocha Barbosa, Eugenia Radulescu, Giulio Pergola, Joo Heon Shin, William S. Ulrich, Amy Deep-Soboslay, Ran Tao, the BrainSeq Consortium, Thomas M. Hyde, Joel E. Kleinman, Jennifer A. Erwin, Daniel R. Weinberger and Apuã C. M. Paquola, 1 November 2022, Nature Neuroscience.DOI: 10.1038/s41593-022-01182-7
