By David N. Leff

Wasn't it Mark Twain who declared: "It's easy to quit smoking! I've done it many times!"?

If Twain were alive today, he'd explain away his nicotine addiction — and frequent relapses from forswearing tobacco — by claiming, "My brain's lateral posterior hypothalamus made me do it."

In other words, he'd be confessing to accepting cerebral bribes. The hypothalamus is reputed to be the brain's bag man, paying out pleasurable rewards — the euphoric buzz of a good cigar — to keep its mark (this time with a small m) hooked.

But behind that carrot, there's a stick.

A person who tries to give up smoking is punished by withdrawal in two ways. The somatic, or "physical," costs of quitting cold turkey may include sweating, dizziness, racing heart, tremor and hunger — hence increased body weight.

"But the emotional signs of drug withdrawal in general," observed psychopharmacologist Athina Markou, "such as anxiety, irritability, inability to concentrate and depression-like symptomology, are longer-lasting than the somatic aspects. What we think is happening emotionally is that the individual tries to self-medicate the depressive symptoms he or she feels because of their withdrawal, by relapsing into resumed drug use. And in this case it's nicotine."

Markou, an assistant professor at the Scripps Research Institute, in La Jolla, Calif., is senior author of an article in this week's Nature, dated May 7, 1998. Its title: "Dramatic decreases in brain reward function during nicotine withdrawal."

"So far," Markou told BioWorld Today, "most of the studies about nicotine and smoking have been done in humans, not animals. And only recently it has been shown that there was a withdrawal syndrome in rats, giving us some kind of a model to study dependence on nicotine — which is one of the ways we define addiction."

When a nicotine-addicted rat is abruptly cold-turkeyed, Markou said, "the findings of its withdrawal have been so far limited to somatic signs — gasping for breath, writhing, noisily chattering its teeth. The reason our work reported in this [edition of] Nature has got some attention is because it has expanded into the more emotional, more affective, aspects of withdrawal.

"It's our working hypothesis," she continued, "that these emotional aspects contribute significantly more to the craving, and relapse into continued drug use, than does the somatic kind of withdrawal."

Nicotine In Same League As Cocaine, Et Al.

Markou and her co-authors have validated this view in rats, not only on nicotine addiction, but with cocaine, amphetamines, morphine and alcohol. "Those tests indicate," she observed, "that even though acute nicotine does not produce as much euphoria as psychostimulant drugs, nevertheless, the symptoms of withdrawal from nicotine are as bad as from the likes of cocaine.

"I would describe this particular paradigm," she went on, "as an animal model of depression, or more specifically of the diminished pleasure the rats get from nicotine withdrawal."

She pointed out that "49 percent of depressed people and 88 percent of schizophrenics smoke. This implies that a subpopulation of smokers are self-medicating depressive symptomology through smoking. So that gives us a hint that maybe nicotine-related compounds will be effective in treating depression or some aspects of schizophrenia.

"And if we're going to develop a behavioral or pharmacological treatment for nicotine dependence," Markou continued, "the focus should be on the more affective aspects of withdrawal, on treating their depression and anxiety and irritability."

Her study was funded in part by Novartis AG, of Basel, Switzerland. That company manufactures a nicotine skin patch to help wannabe ex-smokers kick their habit.

Other support comes from the National Institute of Drug Abuse. That agency's director, Alan Leshner, said of the findings reported in Nature, "Understanding the decreases in the brain's sensitivity to pleasurable stimulation that occur during nicotine abstinence helps explain why it is hard for people to stop smoking. It may also help in the development of better treatments to address the withdrawal symptoms — depression, anxiety, irritability and craving — that interfere with people's attempts to quit."

Virtual Ecstasy From On-Off Switch

When a rat was enrolled in Markou's addiction-ending class, it had an electrode implanted in the presumed pleasure circuit of its hypothalamus. By turning a wheel with its paw, the animal learned to reward itself with a half-second jolt of current that stimulated its sense of euphoria.

"When this pulse is delivered in the hypothalamus," Markou recounted, "it is extremely pleasurable for animals — and for humans too. We could test our rats repeatedly, and they would never say, 'Stop! I've had enough.'"

At the same time, for one week her animals received a steady dose of nicotine by way of an implanted mini-pump. This produced blood levels of the drug equivalent to that of a person smoking 30 cigarettes a day. A less lucky cohort of control animals had to make do on saline injections.

After those seven days of bliss, the rats' nicotine was suddenly cut off, and withdrawal set in. At that point, it took 40 percent more electrical-happiness current before they found the pulses again to be pleasurable. "That 40 percent increase in reward threshold," Markou recalled, "indicated that they needed a more juicy stimulus before they'd say, 'Yes, I like that!'"

In the future, grants willing, Markou and her team will "go in doing injections to sites in the brain that may mediate drug withdrawal. This is based on studies indicating that activation of nicotinic receptors stimulates release of dopamine — which people tend to equate with reward. But that is something of an over-simplification," she concluded. *