Researchers at the University of Copenhagen have gained new insight into the mechanism behind a protein dopamine transporter that could help in the development of future medical treatment against cocaine addiction. With a better understanding of the dopamine transporter function it is expected researchers will become more proficient in developing an antidote against cocaine addiction, for which there is currently no available treatment.
Dopamine is a signaling molecule in the brain which is involved in our sensation of reward, motivation and, thus, addiction. The dopamine transporter functions as a molecular vacuum cleaner removing the released dopamine, thereby controlling its signaling. The dopamine transporter is a protein located in the membrane of dopaminergic neurons. It mediates the re-uptake of released dopamine by coupling its binding to sodium (Na+), using this gradient across the cell membrane as driving force to pump dopamine into the cell.
Also other illicit drugs such as amphetamine (Adderall), methylphenidate (Ritalin) and modafinil (Provigil) work by inhibiting the dopamine transporter. The dopamine transporter is structurally closely related to the transporters for other neurotransmitters such as serotonin, norepinephrine, glycine and GABA.
The researcher’s discovery is an interaction, a so-called gate, which controls access for dopamine to its binding site in the protein. The team found two amino acids in the proteins that dynamically breaks and forms an interaction. The dynamic is therefore crucial for the transport process.
Besides controlling function, the constellation of the two amino acids is important for the overall structure of the protein. The breakage of the interaction could therefore be a signature for the binding of cocaine and cocaine-like drugs.
Once in the brain, cocaine works in large part by occupying, or blocking, dopamine transporter sites in the terminal buttons of neurons in the brain. This prevents the reuptake of dopamine by the neurons that release it, allowing higher concentrations of dopamine to remain in the synapse for an extended period of time and what causes the initial euphoria and reward commonly reported by cocaine abusers.
According to the European Monitoring Centre on Drugs and Drug Addiction, cocaine is the second most commonly used illegal drug in Europe, after cannabis.
Cocaine acts as an inhibitor of the dopamine transporter but the researchers found other inhibitors that even though they did bind to the dopamine transporter with the same strength as cocaine, did not produce the same stimulatory response when administered to rats.
By using molecular pharmacology and biochemistry, they were able to characterize dopamine transporter mutants and how their function deviated from the non-mutated transporter. In contrast to cocaine, the non-stimulatory, or atypical, drugs seem to bind a more closed form of the dopamine transporter.
The team state that if they can figure out, on the molecular level, why they are different then they will be better prepared for the targeted development of non-stimulatory inhibitors that will prohibit the subsequent binding of cocaine and help them towards producing an antidote.
The objective, therefore, is that cocaine will not then work anymore as the antidote will inhibit the stimulatory response of taking this drug.
Source: University of Copenhagen
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