Volume 13, Number 3 (July, 1998)
Like Other Drugs of Abuse, Nicotine Disrupts the Brain's Pleasure Circuit
By Neil Swan, NIDA NOTES Staff Writer
All drugs of abuse disrupt the normal flow of the neurotransmitter dopa-mine, stimulating its release and increasing its brain levels. This action is believed to be significantly involved in producing drug-induced feelings of pleasure and reward and, over time, addiction and vulnerability to withdrawal symptoms. Drugs of abuse begin this action by chemically binding to specific molecular sites called receptors, some of which are found on dopamine nerve cells.
Recent findings from several NIDA-funded researchers confirm not only that nicotine is highly addictive but that it affects the same brain mechanism as other drugs of abuse and increases brain levels of dopamine. The findings also suggest how nicotine abstinence and withdrawal activate the body's stress systems. Two research teams have spotlighted how nicotine, just like heroin or cocaine, activates dopamine-containing nerve cells in the brain's mesolimbic system, which is involved in emotion and behavior. Another group has shown that some brain changes during withdrawal from chronic nicotine use are similar to those that occur during withdrawal from other drugs of abuse.
Dr. John A. Dani of Baylor College of Medicine in Houston and his colleagues have shown that nicotine binds at multiple receptors on dopamine nerve cells, or neurons, to activate the neurons. Theoretically, this activation of dopamine neurons by nicotine begins the response that leads to feelings of pleasure and reward, and then addiction. The researchers examined dopamine nerve cells from the brains of rats that had been exposed to nicotine for prolonged periods. They found that nicotine at levels comparable to those found in human smokers first activates or sensitizes these neurons but then quickly desensitizes them.
The researchers believe nicotine-induced desensitization of dopamine cells may explain why smokers report that they rapidly become tolerant to the effects of smoking during the day. The tolerance fades overnight so that by the next morning the dopamine cells are resensitized to nicotine, the researchers theorize.
"This finding suggests a cellular explanation for smokers' reports that their first cigarette of the day is the most pleasurable," while the pleasurable effect of cigarettes smoked later in the day is greatly reduced, says Dr. Dani. "It's a biophysical extrapolation to explain how the cellular response to nicotine ultimately affects behavior," he explains. The results further support the theory that nicotine acts through the same cellular mechanism as other addictive drugs and that this mechanism - dopamine activity in the mesolimbic system - is implicated in various ways in the cellular and behavioral effects of addictive drugs, he says.
Dr. Marina Picciotto of Yale Medical School in New Haven, Connecticut, and her colleagues in France, Sweden, and Switzerland have gone a step further and have pinpointed the specific protein to which nicotine binds on a particular nicotinic receptor on a dopamine cell.
The researchers used a strain of mouse developed by Dr. Picciotto in which the gene that encodes this protein is eliminated or "knocked out." The researchers found that these knockout mice did not self-administer nicotine as their normal sisters did. The finding suggests that the mice without the protein, called the beta 2 subunit, did not experience the normal reinforcing, or rewarding, effects of nicotine. But the mice did self-administer cocaine, an indication that knocking out the beta 2 subunit affected only their response to nicotine, not to other drugs.
The experiment tested the behavioral response of the mice. But what about their physiological response? If the knockout mice were injected with nicotine, would the nicotine increase dopamine levels? No. In a followup experiment, nicotine injections did not boost dopamine levels in the brains of knockout mice. This finding provided further evidence of the influential role of the beta 2 subunit in the nicotine addiction process. The study findings are consistent with the theory that the dopamine brain circuit is the reward pathway used by all drugs of addiction but that different drugs activate this pathway through different molecular gateways.
"In our altered mice, we've shown that if you take away one subunit of the nicotinic receptor, you take away the ability of nicotine to stimulate dopamine release," explains Dr. Picciotto.
"To actually pinpoint a particular protein shown to be critical to nicotine addiction is a major discovery," says NIDA Director Dr. Alan I. Leshner. Future medications for nicotine addiction might target that specific protein, he says.
Dr. Picciotto is now studying how this nicotinic receptor and its subunits affect the rewarding properties of other drugs such as morphine, cocaine, and alcohol. "People who abuse other drugs are also likely to be smokers, and we would like to know more about interactions between the different systems that mediate the rewarding effects of these different drugs," she says.
Another NIDA-funded study shows that the severity of changes that occur in the brain's pleasure circuits during withdrawal from chronic nicotine use rivals that experienced during withdrawal from other abused drugs such as cocaine, amphetamine, morphine, and alcohol.
The study found dramatically decreased sensitivity to pleasurable electrical stimulation in the brains of rats after nicotine administration was stopped. The decreased sensitivity, which lasted several days, may correspond to the depression experienced by humans who quit smoking "cold turkey."
"Understanding these decreases in the brain's sensitivity to pleasurable stimulation during nicotine abstinence helps explain why it's so hard for people to stop smoking and may help develop better treatments for nicotine withdrawal symptoms such as depression, anxiety, irritability, and craving for a cigarette," says Dr. Leshner. "The brain-change similarities to other drugs of abuse emphasize that there are common characteristics to withdrawal from all addictive substances, one of which is decreased sensitivity to pleasure," he says.
Dr. Athina Markou and her colleagues at The Scripps Research Institute in La Jolla, California, measured the effects of nicotine abstinence on the brain's sensitivity to pleasure-inducing electric pulses. They taught rats to self-administer brief electrical pulses in the lateral hypothalamus, part of the brain's reward circuitry, and then monitored the level of pleasure, or reward, experienced by the animals.
Reward sensitivity measures were taken during and after administration of nicotine. For a week the rats were infused with a steady dose of nicotine to produce nicotine blood levels equivalent to those of a human smoking 30 cigarettes a day.
While nicotine was administered, the animals' sensitivity to brain reward remained stable, as shown by the fact that they self-administered pleasure-inducing pulses at the same level as before nicotine was introduced. When the rats' nicotine was cut off, however, the scientists had to increase the intensity of electrical current by more than 40 percent before the rats showed through their behavior that electrical pulses to the brain were again pleasurable.
"These results are comparable to the altered brain reward sensitivity found during withdrawal from many other addictive drugs," says Dr. Markou. The experiment provides a valid animal model for studying the function of brain reward circuits involved in nicotine withdrawal and to help develop treatments for nicotine addiction, she adds.
Epping-Jordan, M.P.; Watkins, S.S.; Koob, G.F.; and Markou, A. Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76, 1998.
Picciotto, M.R., et al. Acetylcholine receptors containing the b2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173-177, 1998. Pidoplichko, V.I.; DeBiasi, M.; Williams, J.T.; and Dani, J.A. Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390:401-404, 1997.
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