What makes us crazy, really

An Oregon Health & Science University researcher is among an international team closing in on why many people with schizophrenia and other psychotic disorders are “supersensitive” to the powerful neurotransmitter dopamine.

David Grandy, Ph.D., associate professor of physiology and pharmacology, OHSU School of Medicine, co-authored a study appearing recently in Proceedings of the National Academy of Sciences that found a link between dopamine supersensitivity and increased levels of a dopamine receptor with a particularly high affinity for dopamine.

Dopamine is a neurotransmitter found in the brain that plays an important role in the regulation of behavior involved in movement control, motivation and reward, and the dopamine system is thought to be essential to the brain’s response to drugs of abuse, especially opiates and psychostimulants.

Supersensitivity to dopamine, which affects some 70 percent of individuals with schizophrenia, can take the form of a low tolerance to antipsychotics, amphetamines and other drugs, including drugs of abuse, that trigger dopamine’s release in the brain. The latest discovery could someday lead to the development of drug therapies that temporarily bring people with psychosis into a more normal, less-sensitive state and make them more amenable to antipsychotic treatment.

It also could help scientists find ways to turn down the activity of the dopamine D2 receptor in individuals for whom dopamine sensitivity can be dangerous, such as prolonged drug abusers.

“It does appear that wherever you see supersensitivity, you see high-affinity dopamine D2 receptors as the predominant form,” said Grandy, a pioneer in the study of the dopamine neurotransmitter system. “But to say you’re going to then reverse supersensitivity by changing the D2-high status, we haven’t done that. To do that, we have to be able to selectively manipulate the system in such a way that we could drive the receptor from high-to low-affinity or otherwise effect its ability to signal efficiently by some drug treatment.”

While supersensitivity is only determined by observing behavioral changes, and the high-affinity D2 is verified pharmacologically, “what we’re showing is a very strong correlation between the presence of a higher proportion of high-affinity D2 in a population of receptors in animals that show supersensitivity to dopaminergic drugs,” Grandy added.

The study also further confirms the importance of the dopamine system in understanding and treating psychosis.

“The bottom-line, take-home message is that there are a lot of different things that all seem to converge on this system,” Grandy said. “It’s like all roads lead to Rome. The D2 system still seems to be very important in terms of psychosis and amphetamine-mediated disorders.”

To create dopamine supersensitivity in animal models, researchers used mice bred to lack the D2 gene as well as rats treated with PCP, alcohol, amphetamine and other dopamine-inducing drugs. They found that while there were small increases in the total population of D2 receptors among the animal models, the increases were small compared with the jump in densities of D2 receptors in the high-affinity state.

The protein product of the dopamine D2 receptor gene already is the primary target for antipsychotic drugs used to treat schizophrenia, prolonged drug abuse and other diseases with psychotic symptoms. But scientists are only beginning to understand the cascade of events that allow dopamine receptors to signal that they have found and bound the neurotransmitter dopamine.

“The more we understand about the receptors, their physical characteristics, how they put themselves into this high-affinity state, and then signal this event in the brain, the closer we’ll be to better treating and maybe even preventing the development of psychoses,” Grandy said.

From Oregon Health & Science University

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