Selective Serotonin Reuptake Inhibitors (SSRIs)

Sitting here in lab, as usual, I have drugs on the brain. Literally I have been pouring over current literature in an effort to understand the inner workings of the human mind.

The brain houses billions of cells called neurons. Neurons possess electrical activity because they contain charged molecules (ions). When one neuron is stimulated (presynaptic neuron), it releases ions, which carry an electrical signal from one neuron to the next (postsynaptic neuron). Neurons function in networks, connected chemically or functionally. A single neuron may communicate with many other neurons. Sensory experiences trigger electrical activity in neural networks.

There are small and large molecules involved in neural networks. Some small molecules are shown below, while large molecules (proteins) are shown in cartoon representation above. A natural small molecule signal (made by the body) is Serotonin. It is a well-known contributor to feelings of well-being.

The antidepressant selective serotonin reuptake inhibitors (SSRIs) Paxil and Lexapro bind to the monoamine transporter, blocking the mechanism by which serotonin is normally recycled by the presynaptic neuron. The recreational drug Ecstasy sneaks into the neuron through the monoamine transporter, then inhibits the vesicular monoamine transporter (VMAT), resulting in increased Serotonin available for signaling.

Over $400M annual revenue is generated by sales of Lexapro (Lundbeck) while Paxil (GlaxoSmithKline) generates over $800 M. It is interesting to view these molecular structures and think about their similarity and promiscuity. The idea of network interference and stimulation is interesting. Each of these molecules has multiple targets involving cross-talk and transport. Science is only beginning to understand all the inner workings of the mind. But money talks. Should I get a job in the pharma industry? I've always had an interest in unraveling brain chemistry, signaling cascades, metabolism and transport, etc.

Strangely enough, my dear husband is so focused on his work with membrane proteins. Maybe we have a little cross-talk of our own in the research arena. Shown at left is a monoamine transporter (shown in color) in complex with an antidepressant drug (small black structure in center/bottom). If this large coiled structure is unwound (represented below), you would see that it sits in the membrane of the neuron with transmembrane helices and other intra- and extra-cellular domains. The areas of the protein which give specificity to its small-molecule interaction are shown in color.

Finally, I would like to throw a shout out to our friends in Temecula, Leonard and Marcia Bustin who hosted us for a lovely dinner on Sunday. Leonard is in the process of blogging about wine. As always, we had a stimulating conversation over a nourishing meal. We love you guys!