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.

Researchers Find Why Nicotine in Cigarettes May Relieve Anxiety in Smokers

Preclinical data suggests inactivation of a specific sub-class of nicotinic receptors may be an effective strategy to help smokers quit without feeling anxious, according to Virginia Commonwealth University researchers.

These findings could one day point researchers to the development of novel therapies to help smokers quit without feeling anxious.

Smokers use cigarettes for many reasons, but many report that they smoke to relieve anxiety, despite the health danger of cigarette smoking. Researchers are now working to understand the underlying neurochemical pathways that support smoking behavior.

In a study, published online this week in PLoS ONE, researchers observed that low doses of nicotine and a nicotinic receptor blocker had similar effects to reduce anxiety-like behavior in an animal model. They found that inactivation of beta2 subunit, a specific sub-class of nicotinic receptors that bind nicotine, appears to reduce anxiety. This is different from the mechanism that regulates nicotine reward and likely occurs in a separate brain area.

“This work is unique because it suggests that nicotine may be acting through inactivation, rather than activation, of the high affinity nicotinic receptors,” said Darlene Brunzell, Ph.D., assistant professor in the Department of Pharmacology and Toxicology in the VCU School of Medicine.

“Nicotine acts like a key that unlocks nicotine receptors in the brain. Usually that key opens the receptor, but at other times nicotine is like a key that has gotten broken inside of the lock. Our findings suggest that low-dose nicotine may block a specific subtype of receptor from opening that is important for regulating anxiety behavior,” she said, adding that anxiety is a major reason why people relapse to smoking.

Discovery of gatekeeper nerve cells explains the effect of nicotine on learning and memory

Researchers at Uppsala University have, together with Brazilian collaborators, discovered a new group of nerve cells that regulate processes of learning and memory. These cells act as gatekeepers and carry a receptor for nicotine, which can explain our ability to remember and sort information.

The discovery of the gatekeeper cells, which are part of a memory network together with several other nerve cells in the hippocampus, reveal new fundamental knowledge about learning and memory. The study is published today in Nature Neuroscience.

The hippocampus is an area of the brain that is important for consolidation of information into memories and helps us to learn new things. The newly discovered gatekeeper nerve cells, also called OLM-alpha2 cells, provide an explanation to how the flow of information is controlled in the hippocampus.

“It is known that nicotine improves cognitive processes including learning and memory, but this is the first time that an identified nerve cell population is linked to the effects of nicotine”, says Professor Klas Kullander at Uppsala University.

Occupancy of Brain Dopamine D3 Receptors and Drug Craving: A Translational Approach

Selective dopamine D3 receptor (D3R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D3R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D3Rs (OD3R) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)amino] tetralin ([125I]7OH-PIPAT) autoradiography and [11C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D3Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between OD3R and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and OD3R at every time point, and 100% effect at OD3R values greater than or equal to 72%. In humans, a single dose of GSK598809, giving submaximal levels (72–89%) of OD3R, transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher OD3R is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D3R antagonist for the treatment of substance-use disorders.