June 15, 2005
Nicotine And Heroin Activate Same Brain Reward Circuitry

No wonder kicking cigarettes is hard to do.

In experiments with mice, researchers have found that nicotine triggers the same neural pathways that give opiates such as heroin their addictively rewarding properties--including associating an environment with the drug's reward. However, unlike opiates, nicotine does not directly activate the brain's opiate receptors, but activates the natural opioid reward pathway in the brain.

The researchers, led by Julie Blendy of the Transdisciplinary Tobacco Use Research Center (TTURC) at the University of Pennsylvania, said their findings suggest more effective ways that opiate blockers could be used to help smokers quit.

In their experiments reported in the June 16, 2005, issue of Neuron, the researchers administered nicotine to mice and analyzed the levels of a protein called CREB--known to control genes involved in the reward pathway of opiates and other abused drugs. They found that not only was CREB activated in the reward regions of the nicotine-treated animal's brains, but also that the drug naloxone, which blocks the opiate receptors, blocked CREB activation. Also, mutant mouse strains lacking the opioid receptor did not show an increase in CREB activity when they received nicotine.

The researchers also studied the relationship among nicotine, the environment, and this reward pathway. They conditioned mice to associate a specific test chamber with receiving nicotine, finding that the mice would prefer to stay in that chamber when given a choice. The researchers found that just placing the conditioned mice in the chamber activated CREB. They also found that naloxone blocked this conditioned increase in CREB, and that mutant mice lacking CREB or pretreated with naloxone did not show any reward response to nicotine.

However, naloxone did not block the chamber choice of mice conditioned with cocaine, found the researchers, indicating that cocaine activates the brain reward pathway in a different way from nicotine and opiates.

"The present results demonstrate that nicotine-associated environmental stimuli can activate the same molecular signal transduction molecules as the drug itself," wrote Blendy and her colleagues. They wrote that the activation of CREB "is evident not only after acute and repeated nicotine administration, but also following exposure to an environment in which the animal has previously received nicotine."

The researchers noted that clinical studies of opioid receptor blockers to relieve cigarette cravings "so far have produced mixed results, ranging from ineffectiveness at smoking cessation to mild reduction in the desire to smoke."

The researchers wrote that their findings "suggest that the timing and context of opioid receptor antagonist administration are critical for determining the effectiveness of blocking nicotine reward . . . . Given the results reported here, clinical studies designed to evaluate administration of opioid antagonists just prior to cues associated with smoking could lead to a more promising treatment regimen."

The brain reward system is effectively hijacked by recreational drugs. Normally the brain reward circuitry activates to encourage adaptive behavior such as getting food and doing other life-promoting work. Addictive drugs that activate reward circuitry drugs are dangerous because they subvert the purposes of the reward system and reduce or eliminate the motivations for adaptive behaviors.

Note that animals can be conditioned to associate being in a particular room with getting a reward. When medical treatments that control reward responses are developed they'll be used to cure drug addictions. But the understanding of brain reward circuity resulting from addictive drug studies will also point the way toward the development of treatments which can be used to manipulate human behavior in sophisticated ways. Will the greater use of such treatments be by governments and other entities to manipulate the behavior of individuals? Or will individuals use such treatments to manipulate their own behavior?

Self manipulation might sound counter-intuitive at first. But we all end up doing things we think we shouldn't do while at the same time we don't do other things that we think we really ought do so. So will the frontal lobes of our brains choose to administer treatments to ourselvse that realign the motivations of other parts of the brain? Picture the forebrain exclaiming "Bow to me now limbic system. You are no longer in control. I am finally your complete master."

Once the neurotechnologies exist to control rewards I expect a lot of people to modify their reward systems to favor the pursuit of longer term goals. As I've previously argued I also expect people to selectively turn off love as a motivation when they find that feeling stands in the way of reaching their goals.

Share |      Randall Parker, 2005 June 15 03:35 PM  Brain Addiction

Wonka said at June 16, 2005 7:04 AM:

"The brain reward system is effectively hijacked by recreational drugs. Normally the brain reward circuitry activates to encourage adaptive behavior such as getting food and doing other life-promoting work. Addictive drugs that activate reward circuitry drugs are dangerous because they subvert the purposes of the reward system and reduce or eliminate the motivations for adaptive behaviors."

Do you include nicotine (and smoking) in this assert? As an ex-smoker with (I assume) not a bad history of addaptive behaviors, it is very difficult for me to believe that nicotine "subvert the purposes of the reward system...". Maybe it just subvert them a little. Thank you very much for your blog, it is always very informative and thought-provoking.

Braddock said at June 16, 2005 7:44 AM:

RP is exactly right about subversion of the reward system by drugs, including legal drugs like cigarettes/nicotine, and alcohol. Caffeine does the same thing through different receptors. Chocolate is a milder example, (and food itself, especially high calorie low nutrition foods, also hijack the reward system). Cigarettes also work through the cannabinoid receptors, which explains the rationale behind the new french(?) drug to stop smoking by blocking cannabanoid receptors.

The thing that worries me is the early age at which so many kids are using mind altering drugs, long before the brain can start to mature. Not only crack babies and children of alcoholic mothers and smokers are permanently damaged. Even if the mother did everything perfectly during her pregnancy, if the juvenile starts using drugs in the fifth grade, the damage still occurs.

Randall Parker said at June 16, 2005 8:31 AM:


You are right that nicotine is different in the sense that cigarettes do not demotivate people away from work and other adaptive activities. People often smoke while they work.

On the other hand, the reward system is hijacked to cause people to engage in the destructive behavior of smoking which damages much of the body.

What I'd like to know about smoking and work is to what extent does the carbon monoxide and other toxic compounds interfere with the brain's function? Does the nicotine focus the mind (or at least end the distraction of thinking about the cigarette) even as the toxins decrease its efficiency?

The other point about smoking and maladaptive behavior is that going out to have a cigarette does take time away from working. I collaborate with a smoking addict and we'll be working at the computer and he'll have to get up to go outside to light up. These 5 to 10 minute interruptions add up.

Braddock said at June 16, 2005 9:10 AM:

Nicotine by itself seems to be neuroprotective up to a point. Some neurological diseases seem to be less common in smokers.

Schizophrenics function better with nicotine than without it. Anyone who has ever observed schizophrenics would probably agree. Something similar is probably at work in non-schizophrenics. The agitation observed in people quitting cold turkey probably involves some dopamine receptors, as well as opioid and cannabinoid receptors. In other words, to get a small feeling of what schizophrenics experience all the time, get a tobacco habit and then quit cold turkey.

Wonka said at June 16, 2005 1:16 PM:

Braddock, it's not that difficult to quit cold turkey. You just do it (I smoked some thirty cigarettes a day). It's not heroine or cocaine or crack. In fact, most of the people that quit smoking do it cold turkey, without help from nicotine replacements or antidepression drugs (bupropion et al.). But Randall Parker is right in that nicotine engages you in a rather risky behavior, so his argument holds, to some extent.

DMAC said at July 24, 2005 3:54 PM:

I have to disagree with Wonka. Quitting smoking is NOT as easy "just quitting". Nicotine is a highly addictive and insidious drug. I say insidious because tobacco is everywhere. Like an alcohic trying to quit drinking, you can find cigarettes(or alcohol)anywhere at any time and noone can stop a person of legal age from buying them. I have been smoking heavily for 25 yrs and am interested in naloxone to see how it would work in combination with other methods to produce a more effective "stop smoking" regimine.
I have tried many, many times to quit and I have failed every time. I don't see myself as a weak-willed person. Nicotine is addictive in many different ways and some people can break the addiction easier than others.

Tony James said at April 4, 2006 1:38 AM:

That's great! It's always inspiring to see the support for people who wants to quit smoking. I have been an ex-smoker myself for 15 years. That is why I know exactly how it feels and also how to deal with the withdrawal symptoms and the psychological aspect of it.

I now publish a newsletter to help people quit smoking with ease without the discomfort of cravings.

It is at:


Feel free to subscribe to it =)

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