A Fresh Look at Psychiatric Drugs
For several years, Henry Lester, Bren Professor of Biology at Caltech, and his colleagues have worked to understand nicotine addiction by repeatedly exposing nerve cells to the drug and studying the effects. At first glance, it’s a simple story: nicotine binds to, and activates, specific nicotine receptors on the surface of nerve cells within a few seconds of being inhaled. But nicotine addiction develops over weeks or months; and so the Caltech team wanted to know what changes in the nerve cell during that time, hidden from view.
The story that developed is that nicotine infiltrates deep into the cell, entering a protein-making structure called the endoplasmic reticulum and increasing its output of the same nicotine receptors. These receptors then travel to the cell’s surface. In other words, nicotine acts “inside out,” directing actions that ultimately fuel and support the body’s addiction to nicotine.
"That nicotine works ‘inside out’ was a surprise a few years ago," says Lester. "We originally thought that nicotine acted only from the outside in, and that a cascade of effects trickled down to the endoplasmic reticulum and the cell’s nucleus, slowly changing their function."
In a new research review paper, published in Biological Psychiatry, Lester—along with senior research fellow Julie M. Miwa and postdoctoral scholar Rahul Srinivasan—proposes that psychiatric medications may work in the same “inside-out” fashion—and that this process explains how it takes weeks rather than hours or days for patients to feel the full effect of such drugs.
"We’ve known what happens within minutes and hours after a person takes Prozac, for example," explains Lester. "The drug binds to serotonin uptake proteins on the cell surface, and prevents the neurotransmitter serotonin from being reabsorbed by the cell. That’s why we call Prozac a selective serotonin reuptake inhibitor, or SSRI." While the new hypothesis preserves that idea, it also presents several arguments for the idea that the drugs also enter into the bodies of the nerve cells themselves.
