Scripps Scientists Successfully Test Potential New Smoking Cessation Treatment in Rodents

Scripps Research scientists have successfully tested a new potential treatment for smoking cessation in rodents.

In a study published online in Progress of science On October 17, 2018, scientists endowed nicotine-dependent rats with a modified enzyme that breaks down nicotine in the bloodstream before it reaches the brain. The treatment quickly reduced animals' motivation to take nicotine, reversed their signs of nicotine addiction and prevented them from relapsing when they again had access to nicotine.

"It's a very exciting approach because it reduces nicotine addiction without causing cravings and other severe withdrawal symptoms. It works in the blood, not in the brain. Its side effects should be minimal, "says lead researcher Olivier George, PhD, associate professor at Scripps Research.

Nicotine addiction is what makes smokers smoke despite all the harm they do to their health. Researchers estimate that about 60% of people who try to smoke become daily smokers – and about 75% of daily smokers relapse after quitting.

Reversing nicotine addiction by preventing nicotine from tobacco smoke reaching the brain has long been considered a promising strategy. However, previous efforts have failed to develop drugs that sufficiently reduce blood levels of nicotine to be effective.

The enzyme tested in this study, NicA2-J1, is a version of a natural enzyme produced by the bacterium Pseudomonas putida. It has been modified – to optimize its potency, its blood residence time and other pharmacological properties – by the laboratory of Kim Janda, PhD, chair Ely R. Callaway, Jr. of Chemistry at the Scripps Research. Studies published in recent years by Janda and colleagues have shown that NicA2-J1 strongly reduces blood levels of nicotine in rodents and that it is effective in a simple model of nicotine addiction in rats.

For the new study, the researchers tested the enzyme in more sophisticated animal models, developed in George's lab, that better mimic the smokers' reliance on nicotine.

For a series of experiments, laboratory rats spent 21 hours a day, for 12 days, in a room where they could press a lever to get an intravenous nicotine infusion. In this way, they learned to self-administer nicotine and became addicted to it. After 12 days, they had access to nicotine every 48 hours, which led them to experience weaning symptoms between periods of access and to increase their consumption – a classic sign of increased smoking. dependence – every time they came back.

Animals treated with the highest dose of NicA2-J1 (10 mg / kg) continued to self-administer nicotine when they could, but had very low blood levels of the molecule compared to to controls not receiving the enzyme. Signs of nicotine withdrawal, such as pain sensitivity and aggressive behaviors, were reduced accordingly during periods of no access, compared to untreated controls.

"It's like they were smoking 20 cigarettes but were receiving the nicotine dose of only one or two, which made their withdrawal process much less severe," says the first author of the study, Marsida Kallupi, PhD, Postdoctoral Researcher at the George Laboratory.

Surprisingly, even the acute effect of NicA2-J1 on rats taking nicotine was benign. Generally, when an animal is highly dependent on nicotine, receiving a drug that suddenly blocks any nicotine activity immediately triggers withdrawal symptoms. "It's like leaving the cold turkey – the subject will be horrible," says George. "However, what is unique about this enzyme is that it eliminates enough nicotine to reduce the level of addiction, but leaves enough to prevent animals from experiencing severe withdrawal."

One of the other characteristics of nicotine addiction is the pursuit of nicotine research despite serious adverse consequences – consequences for smokers who smoke to include short-term changes in lung function and physical fitness, as well as long-term risks of cancer, heart disease, stroke and many other ailments. George, Kallupi and colleagues have shown that NicA2-J1 could reduce this compulsive nicotine motivation in dependent rats. When each pressure on the nicotine lever is also 30% more likely to receive electric shock to the feet, the NicA2-J1 treated rats – unlike the untreated controls – quickly reduced their pressure on the lever.

Scientists have modeled another key aspect of nicotine addiction, susceptibility to relapse after abstinence: they removed rats from nicotine for 10 days, then gave them a nicotine injection to revive their nicotine addiction. desire to take the drug, lever presses. Untreated rats that were primed in this manner increased their leverage significantly – NicA2-J1-treated rats significantly less. The same beneficial effect of NicA2-J1 was observed when the researchers triggered a relapse with a stress-inducing drug, mimicking the way in which stress causes a relapse in humans.

With such promising results in preclinical testing, the Scripps research team now hopes to include NicA2-J1 in human clinical trials. Before that, scientists would continue their work to optimize the properties of NicA2-J1 as a drug. They also plan to test it in rats against Varenicline (Chantix), a compound that blocks the activity of nicotine in the brain and is currently considered the most effective anti-smoking drug.