THE DRUGS DON'T WORK: Variations in the gene that codes for the D2 receptor protein could influence the way certain antipsychotics work in the brains of mentally ill patients.
Alterations in the genetic coding for a nerve cell receptor, which detects a chemical signal that is key to behavioral change, could point the way to designing therapies most effective for patients suffering from schizophrenia, drug addiction and other mental illnesses.
"I don't know if what we just published is a viable biomarker," says Wolfgang Sadee, chair of the Department of Pharmacology at The Ohio State University (O.S.U.) College of Medicine and the co-author of a report on the finding published this week in Proceedings of the National Academy of Sciences USA. "But, I think there's a good chance that this is a biomarker that we will at least test and we will know soon if there is something worthwhile."
A team of scientists from O.S.U. examined 68 samples of postmortem tissue from the brains of people without a history of mental illness in search of the profile of messenger RNA (mRNA) transcribed from a particular gene. (mRNA is the intermediate blueprint between gene and protein.) Researchers were specifically hunting for the mRNA created from the two alleles (copies) of the gene DRD2, which codes for a receptor protein for the neurotransmitter dopamine. D2 dopamine receptor malfunction has been linked to drug addiction, schizophrenia and Parkinson's disease. The team focused its search on the striatum (a midbrain region implicated in planning and movement) and the prefrontal cortex, the brain's central processing area.
In 15 of the brain samples, researchers found that one copy of DRD2 was producing at least 50 percent more mRNA than the other one; in the remaining brains, they discovered that both alleles produced equal amounts. They also identified SNPs (single nucleotide polymorphisms, or alterations to the genetic code created by the addition or deletion of a single nucleotide in a gene's long chain). Two of these changes caused differences in the protein made by the gene; one of them appeared to be the result of DRD2 gene being spliced together differently, resulting in a protein consisting of a slightly longer than normal chain of amino acid building blocks.
The unexpected finding of a splice variant caused some excitement in the lab, Sadee says, because, according to the literature "the short form is more inhibitory and the long form may be facilitating dopaminergic transition. … When dopaminergic input comes in, [individuals with the SNPs on one gene copy] would have a chance of having more transmission" than those with two normal copies of the gene.
Sadee contacted Alessandro Bertolino at the University of Bari in Italy, who was doing research that involved monitoring the brain activity of 117 volunteers with functional magnetic resonance imaging (fMRI) during memory tests. Seventeen of the subjects in Bertolino's pool carried the SNPs on a single allele and showed increased activity in their striata and prefrontal cortices during the mental exercises, yet performed worse on the memory tests and had less attention control than the other study participants.
Sadee speculates that the brains of these subjects may be in "unnecessary hyperdrive. The dopamine stimulates more activity and that relates to more brain activity during a memory task," he says. "That is maybe not as good as memory function. … The brain has to work harder to master the same task, and that's induced by this polymorphism."
He says the study could improve current treatments for patients suffering from mental illnesses. The proper antipsychotic drugs may in the future be determined by genotyping patients to assure the most positive effect. Physicians now often have to try out different drugs to test their effectiveness, because this class of medications is highly varied and targets different brain receptors. Such findings as these could dramatically reduce the guesswork involved, thereby leading to the proper prescription from day one. Currently, Sadee says, antipsychotics are only effective 50 to 60 percent of the time and take five to six weeks to begin working.
"The influence of antipsychotics that inhibit D2 antagonist activity will differ between the two" forms of the protein receptor, he says. "One is facilitating and the other inhibiting, so the net effect of inhibiting the D2 receptor will change. So, we think that is one possible mechanism for differences in antipsychotic response."
