Dr. Zahniser was strongly committed to mentoring young scientists and showed deep satisfaction in seeing her graduate students and postdocs blossom and become independent researchers. This symposium was organized by people who were influenced and/or trained by Nancy, and who are grateful for her guidance. As a tribute to her many contributions the speakers highlighted the role of the dopamine transporter in health and addiction, a topic Nancy researched extensively. I summarize two of the symposium presentations below concerning a previously unknown mechanism of action for amphetamine, and the use of PKC inhibitors to limit the dopamine release caused by psychoactive drugs.
The urge to enjoy some comfort food or to listen to your favorite song is caused by dopamine- a chemical messenger that neurons release in the brain when you do something you like. Dopamine is also known as the “motivation molecule” because it makes you want to do the things you enjoy again and again. The impulse to repeat pleasant experiences ends when a protein known as the dopamine transporter clears dopamine from the outside of the neurons, and the cells that originally produced it store it for later use.
Cocaine and other drugs of abuse hijack this system. They generate drug-seeking behavior by blocking the dopamine transporter, which prevents the removal of dopamine from the outside of the cells and ultimately causes both the feeling of euphoria and the intense urge for more drug.
A widespread practice of drug users to achieve a greater high consists in combining cocaine and amphetamine, a psychostimulant used to treat attention-deficit disorder. Unlike cocaine, which simply blocks the dopamine transporter, amphetamine enters neurons in the brain either through the dopamine transporter or by diffusion across the cell membrane. Once inside, amphetamine causes dopamine to escape through the dopamine transporter into the fluid outside the cells. When combined with cocaine, amphetamine diffuses into neurons. However, dopamine can’t escape into the fluid outside the cells because cocaine is blocking the transporter. This creates a conundrum as to why this drug combination produces a greater high.
Dr. Lynette Daws from the University of Texas Health Science Center at San Antonio hypothesized that amphetamine could be acting through an alternative mechanism, and she turned her attention to Organic Cation Transporter 3 (OCT3), a protein that transports chemical messengers inside the brain including dopamine.
One of the short-term effects of amphetamine in people with a normal dopamine circuit is hyperactivity. Her group showed that OCT3 is present in neurons that produce dopamine, and that inhibiting the action of OCT3 using a drug called decynium-22 prevented hyperactivity in mice after treatment with amphetamine, indicating that amphetamine might also be using OCT3 to pump out dopamine.
Her work offers an explanation as to why combining cocaine and amphetamine generates a greater high than either drug alone. Even though cocaine blocks the dopamine transporter, amphetamine still gets into neurons by diffusion. Release of dopamine into the outside of the cells still occurs through OCT3, so even if cocaine blocks the dopamine transporter, dopamine is still able to escape into the fluid outside the neurons.
Dr. Margaret Gnegy from the University of Michigan talked about a different mechanism that explains how amphetamine increases dopamine release. Amphetamine induces the release of dopamine by activating a protein known as protein kinase C (PKC). When her group administered either amphetamine or cocaine together with drugs that inhibit PCKβ- a subclass of PKC proteins- into the brains of mice, they were able to reduce the amount of dopamine content outside of the cells in the brain, as well as inhibit the hyperactivity associated with both amphetamine and cocaine. Her work shows that PCKβ is an important target to develop drugs that can treat addiction.
Dr. Zahniser pioneered research that showed how dopamine contributes to the changes that cocaine produces in the brain, including addiction-like behaviors. This symposium captured important advances in our understanding of how drugs of abuse hijack the brain’s reward system as well as new targets that we can investigate further to develop new treatments for addiction.
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