Chemical of love, creativity and addiction

A study shows that the new designer drugs that mimic one of the main effects of drug dopamine on the brain trigger a structural change in a receptor for this neurotransmitter and, therefore, produce a well-controlled high.

Gene mutation in human dopamine neurons causes a protein to be translated incorrectly and over-produce dopamine in the brain. This over-expression of dopamine leads to the onset of mania and psychosis. By itself, this phenotype is harmless, but it could be dangerous in patients with Parkinson's disease, and in young people before they have experienced their first sexual attraction. A study published in Nature Neuroscience shows that the new designer drugs that mimic one of the main effects of drug dopamine on the brain trigger a structural change in a receptor for this neurotransmitter and, therefore, produce a well-controlled high. This so-called drug-induced response (DIR) regulates psychotic symptoms in rodent models and could therefore play a key role in the development of new psychostimulant drugs. Around one in twenty people of whom around one in thirty have schizophrenia are taking dopamine-based drugs such as those used to treat schizophrenia or Parkinson's disease. But dopamine is a complicated molecule that can exist in different forms inside the brain. When the brain cells (neurons) that release dopamine release too much or too little dopamine the symptoms of mental health problems are mediated by the concentration of the drug in the brain. These symptoms often do not begin until the first exposure to the drug. In people without a dopamine-based mental health problem, there is no over-expression of dopamine that can be exploited for therapy. To date, most research into designer drugs has focused on the effects on the brain of dopamine receptors but has rarely considered how the receptors become activated and whether they are also activated by other proteins that can provide the signal that causes the release of dopamine. It is unclear, therefore, how designer drugs can target the symptoms of mental health problems. A common approach is to investigate drugs that can inhibit dopamine neurons. Such drugs are of limited use for treating mood disorders because the brain can only get rid of dopamine in a particular way. This process occurs when cells break dopamine down into a form that the brain can use and produce a further dopamine molecule that triggers a craving for the drug. However, the problem is that the risk-benefit ratio of using such drugs is not well understood. They also take time to get into the brain and their effectiveness can diminish over time. One alternative is to develop a dopamine-based drug that can switch off certain dopamine neurons selectively and over a short period of time. This is known as an anticonvulsant or anticholinergic drug. The problem is that there is very little understanding of what goes on in the human brain when dopamine neurons are activated. A common target of such drugs is the receptor that recognizes dopamine in the brain: the G protein-coupled receptor G-protein (GPCR). It is known that once activated, a GPCR forms a complex with a number of proteins that seem to support the conversion of dopamine to another neurotransmitter called acetylcholine. To produce its effect, the drug attaches to a specific part of the receptor and, in doing so, changes the conformation of the receptor. This changes the amount of its receptor that can bind with the drug and, therefore, the ratio of the drug that can be released. By changing the activity of the receptor, it can reduce the number of dopamine molecules it is linked to and thereby reduce the number of symptoms produced by the drug. As part of a project funded by the Medical Research Council (MRC), researchers from Imperial College London worked with colleagues in the School of Life Sciences to explore how the conformation of the GPCR, called D4R, is changed by exposure to dopamine. The group found that, when the receptor is activated by dopamine, it forms a complex with a protein called FKBP53. When dopamine attaches to the receptor, it also forms a protein complex called the GPCR protein tyrosine kinase receptor (GPR40). This produces what is known as an agonist-activated receptor tyrosine phosphatase (AAR). The AAR then requires the presence of another protein called PRKAG2 to ensure that the receptor is switched off again after the dopamine has been released. When the researchers added a drug that degrades the ability of the PRKAG2 protein to help with this process, the receptor was reduced in the amount of the receptor that could be bound by dopamine. The drugs did not affect the amount of GPR40 that was able to form a complex with the receptor. This effect was reversible, which is important because it shows that the drug-induced receptor dimer does not last long enough for it to have an effect. As a consequence, the GPR40 remains switched on and makes it possible for the drug to bind to the receptor again. "Many people feel that the problem with drugs of abuse is that they make you feel good when really the effects are just as bad for you. The receptor is activated by dopamine, its ability to inhibit another protein, PRKAG2, to return the receptor to a closed state is also reduced. This is what creates the impression that the drug reduces the effects of the drug on the brain. As a result, the drug may take longer to get out of your system, the often long-lasting changes in how you feel if you take a drug that was designed to treat one problem and actually causes new problems as a side-effect." The team now plans to use genetic and other techniques to see whether specific proteins are linked to the effects of designer drugs. This will allow them to examine how drugs can target receptors to produce unwanted side-effects. "With some types of drug, such as cocaine, we know that drugs like cocaine bind to particular parts of the receptor in our brain. These parts of the receptor are known as 'entrants'. Drugs like cocaine bind to the 'entrants' and their binding prevents the receptor from being able to bind to other parts of the receptor and, therefore, reducing the activity of the receptor," explains Dr. Richard Winslow, senior author of the study. "In the future, we can investigate what proteins can 'lock' and 'unlock' the receptor and this will help us to understand what effects these drugs have on us."