Modulation of Dopamine Transporter Function by Tamoxifen

Abstract

The neurotransmitter dopamine is vital to motor coordination, reward, motivation, and cognition. Diseases of dopaminergic dysfunction include Parkinson’s disease, addictions, and bipolar disorder, to name a few. The dopamine transporter is responsible for the reuptake of extracellular dopamine and as such plays a key role in modulating the strength and duration of the dopamine signal. Due to its role in dopamine regulation, the dopamine transporter is an attractive therapeutic target for pharmacological intervention in diseases of dopaminergic dysfunction. This dissertation presents results that support the repurposing of an old drug for a novel purpose. I demonstrate for the first time that the breast cancer therapeutic tamoxifen, widely investigated and prescribed for its role as a selective estrogen receptor modulator, is an atypical blocker of the dopamine transporter. Atypical dopamine transporter blockers are currently under investigation for the treatment of psychostimulant abuse due to their unique ability to antagonize the actions of cocaine and amphetamine at the dopamine transporter without exhibiting their own abuse liability. Here, I show that tamoxifen non-competitively inhibits dopamine uptake and amphetamine-stimulated dopamine efflux. This action at the transporter is independent of tamoxifen’s effects on the estrogen receptors and appears to involve a direct interaction of tamoxifen with the S2 binding site of the dopamine transporter. Consistent with my assertion that tamoxifen is an atypical dopamine transporter blocker, I found that tamoxifen attenuates amphetamine-stimulated hyperactivity, yet exerts no stimulant effects on its own. Further investigation into the active metabolites of tamoxifen revealed that 4-hydroxytamoxifen and endoxifen also impede dopamine uptake and amphetamine-stimulated dopamine efflux. Interestingly, these two compounds seem to act asymmetrically on the dopamine transporter, preferentially inhibiting dopamine uptake and amphetamine-stimulated dopamine efflux, respectively. I propose that tamoxifen, or a novel chemical based on its structure, may present a viable option for the treatment of psychostimulant abuse.