According to the European Monitoring Centre on Drugs and Drug Addiction, cocaine is the second most commonly used illegal addictive in Europe, after cannabis. A discovery related to the mechanism behind a dopamine transporter could help in the development of future medical treatment against cocaine addiction.
Dopamine is a signaling molecule in the brain which is involved in our sensation of reward, motivation and thus, it is assumed, addiction. 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. Other 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 discovery is an interaction, a so-called gate, which controls access for dopamine to its binding site in the protein.
"We found two amino acids in the proteins that dynamically breaks and forms an interaction. The dynamic is therefore crucial for the transport process," says Loland. "If we have a better understanding of the dopamine transporter function we will become more proficient in developing an antidote against cocaine addiction," says Associate Professor Claus Juul Loland from the department of Neuroscience and Pharmacology.
Currently there is no available medical treatment for cocaine addiction. 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."
Towards a cocaine antidote
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. 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 re-uptake 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.
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.
If the researchers 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.
"Our objective here is that cocaine will not then work anymore as the antidote will inhibit the stimulatory response of taking this drug," concludes Loland.
The results have been published in the Journal of Biological Chemistry.