Tamoxifen affects dopamine transport

What is it about?

Many studies have shown that the selective estrogen receptor modulator, tamoxifen, affects neuronal dopamine. For instance, tamoxifen is protective against toxicity induced by the dopamine transporter (DAT) ligand, MPP+. By measuring forward and reverse transport and direct binding, we investigated if tamoxifen would directly affect DAT function. In a preparation of dopamine nerve endings (synaptosomes) we showed that tamoxifen dose-dependently inhibited dopamine uptake and amphetamine-stimulated reverse transport through DAT. Tamoxifen weakly inhibited binding of a cocaine analog to DAT, suggesting that the drug could bind to DAT, but not strongly. By examining the accessibility of a certain cysteine to the environment, we found that tamoxifen likely stabilized an inward-facing conformation of the transporter, in such a way as to slow the in and out passage of dopamine through the protein. Moreover, through the use of selective mutants, it appears that tamoxifen interacts with a secondary substrate binding site in the transporter. Interestingly, tamoxifen elicited no change in locomotor behavior when given alone to rats, but inhibited hyperactivity stimulated by amphetamine.

Featured Image

Why is it important?

Our long-term goal is to design a drug that would inhibit amphetamine neurochemical and behavioral actions. Because of its ability to cross the blood brain barrier and interfere with amphetamine-stimulated neurochemical and behavioral actions, tamoxifen may serve as a good scaffold for a drug to reduce amphetamine abuse.