By David N. Leff

Of all weight-controlling drugs on the market today, the most popular is nicotine.

Cigarette sales have dropped of recent years among men, but continue to escalate among girls and women. Tobacco advertising depicts slender, svelte young females in the act of smoking.

That act ensures that their body weight stays 5 percent to 7 percent below what it would be had they never taken up the habit. And when they try to kick it, said behavioral pharmacologist Stephen Heinrichs, of Neurocrine Biosciences Inc., in San Diego, “three out of four people report the unwelcome weight gain that accompanies the sudden abstinence syndrome.“

In contrast, Heinrichs continued, “girls and women who smoke and have a constant blood level of nicotine, are enjoying a relative reduction in their normal body weight. In other words, it’s not only the rebound, but losing the beneficial, attractive and highly desirable ideal body image in the anorective effects of the nicotine, when it’s on board.“

These two factors together — by a negative reinforcement mechanism — are thought to strongly motivate the smoker to return to cigarettes.

After saying no to nicotine, Heinrichs pointed out, the most salient compensatory side effect is hyperphagia — compulsive over-eating. “If you interviewed a sample of recently abstinent smokers,“ he told BioWorld Today, “the most significant aspect they’d report to you would be their intense craving for food, particularly sweets. This craving,“ he added, “is thought to share a lot of properties with drug craving, in that it appears to tap in to some of the reinforcement circuits of the brain that determine highly motivated behaviors.“

Heinrichs is first author of a research article on the uncontrollable urge to overeat, in the current Proceedings of the National Academy of Sciences (PNAS), dated Dec. 24. Its title: “Corticotropin-releasing factor [CRF]-binding protein ligand inhibitor blunts excessive weight gain in rats during nicotine withdrawal.“

Elevated CRF in the brain correlates with reduced food intake and body weight gain in normal and obese animals.

A cohort of normal animals, three months old and weighing 300 to 350 grams, (1.4 to 1.6 lb.) received nicotine systemically by subcutaneous infusion for two weeks, Heinrichs related, “in such a way that their blood levels of the psychostimulant mimicked those of a two-pack-a-day smoker.“ At this point, the rate at which they put on body weight dropped by 5 to 10 percent.

Then, when withdrawn from the drug and given a CRF-binding inhibitor, they experienced a 35-percent appetite suppression and 25 percent reduction in the rate at which they put on weight. Over two weeks, they gained about 20 grams per week.

After two weeks of abstinence withdrawal without CRF-inhibition treatment, “Hyperphagia kicked in. This resulted in exaggerated weight gain, which normalized when they reached the same body weight at which their control cohort had been at the beginning of the study, four weeks earlier.

“However, those rats treated with CRF inhibitor did not,“ Heinrichs observed.

Next, he went on, “I would like to see this treatment evaluated in models of carbohydrate craving, and in nicotine detoxification programs, in which smokers are trying to terminate their habit.“

Neurocrine, he added, is working on “a small-molecule, non-peptide compound to mimic the actions of these centrally administered peptides, namely, CRF-binding inhibitors. Its target would be a receptor located, for instance, in the vegetative, hypothalamic region of the brain. And it would be administered orally, as a pill.“

The company, he concluded, “recently set up a collaborative partnership with Eli Lilly & Co., of Indianapolis, to achieve exactly that drug discovery goal. It’s based on the outcome of our Zucker rat experiments.“ (See BioWorld Today, Oct. 22, 1996, p. 1.)