Retrospectacle: A Neuroscience Blog

Most people who have known a drug addict, or have watched Trainspotting or ER, know that one of the more insidious parts of addiction is the need for more and more drug to achieve a “high.” This leads the addict into a spiral of drug-seeking behavior, and brain changes, which lead to the person just trying to feel normal again. Why is it that, over time, opiate drugs lose their rewarding effects? Until recently, the molecular mechanism behind “why” was unknown, but a new study published in Nature (subscription required) this month explains that has to do with the decrease of a certain signaling pathway in the dopamine reward system.

Consider this: In the 1950s, a scientist named Wikler conducted an experiment to measure the intake of morphine of a addict who was given free access over 100 days (clearly this could not be repeated today!). He found that addicts increased their drug intake from around 50mg in the beginning, to over 1400mg after 100 days! Animal studies which allow rats to press a lever to receive an opiate also increase their lever-pressing activity over time, often to the exclusion of everything else in their environment–food, water, sleep. Both humans and animals display a tolerance to the drug over time, they become less and less sensitive to the opiate’s actions and require more drug to achieve a baseline feeling.

In a model of chronic opiate exposure, just one day after withdrawl from morphine there is a 25% decrease in the ventral tegmental area (VTA) neurons but not other neurons. This effect can be reversed by the growth factor BDNF, which signals through 3 pathways: the protein insulin receptor substate 2 (IRS2), phospholipase C y, and the extracellular signal regulated kinase (ERK) pathway. So, it would follow that the decrease in dopaminergic neurons, brought about by opiate withdrawl, was induced by one of these pathways. But which one?

Through an impressive array of behavioral and molecular experiments, Russo et al discovered that the responsible party was the IRS2-Akt pathway. They even determined that injections into the VTA of chemical depressants to the IRS2 pathway resulted in decreased morphine reward just like chronic morphine administration, while chemical stimulants of the pathway enhanced reward. All this suggests that morphine abuse downregulates this pathway in the VTA neurons, resulting in decreases in VTA dopamine cell size which lead to tolerance.

This data is preliminary and awaits further clarification of the pathway, and how it generalizes to people. However, it is quite possible that a new method of treating addiction could be developed from these results.

Comments

#1 Bram Cohen
December 31, 2006

If I may ask a dumb question, how best would one use this for making a treatment for drug addiction? If you enhance the feedback loop, you could reduce tolerance, which would make the person use less of the drug, and probably do a lot less damage to themselves, but still be an addict. If you send a signal down the pathway which has the feedback loop directly, then it *might* make people no longer need the drug at all, although that *might* be ‘substituting one drug for another’, but it’s unclear whether withdrawal symptoms would then be easier or harder to deal with, and whether the substitute drug would have less or more side effects.

If, in the opposite direction, you decrease the strength of the feedback loop, then that may in the extreme cause the drug to simply stop working, and get rid of the positive feedback loop. On the other hand, it may just cause the person to need more of the drug and be more addicted. The one direction of treatment which seems clearly promising would be to try giving something to increase tolerance dramatically to someone who has just gone through detox, to reduce the chances of them becoming re-addicted.

Past experiences with these sorts of things are kind of depressing – most treatments which sound logical wind up making the problem worse in unexpected ways.
#2 Koray
December 31, 2006

I find this subject very interesting. What book would you recommend to a person without any neuroscience background? I am not interested in the likes of books that aim to help addicts; I just want to educate myself.
#3 Kagehi
December 31, 2006

Not sure if its mythical or real, but I have heard of a drug, which *is* mentioned in several shows like Law And Order, which had an interesting side effect. While it caused someone to get high, it also *reset* the pathways somehow, causing them to lose the addiction they had to what ever drug they where on. The problem in a nut shell was that the anti-drug idiots all went, “Gasp!!! We can’t do that! People might start just taking this new drug, and without the misery, death, disease, withdrawal symptoms, not to mention the *unmnetioned* rapes, murders, muggings, thefts, multi-million dollar drug running businesses, etc, it would be somehow worse than it is now.”

I.e., if taking it cured addiction entirely and their where no apparent consequences of using it, it might somehow become some horrible new drug (instead of just a *true* recreational one, which the so called recreational ones we have now are anything but), who gives a shit about the thousands of people that die world wide on a monthly basis due to the trade, the vast cost of treating the people we do treat, the nearly incomprehensible failure of “fighting” it, etc. Things should have consequences. Drugs are bad, so they should have consequences and any that “could” be taken safely, or used to cure a large percentage of existing addicts, is “even worse”, instead of something we should be providing to every damn clinic on the continent and beyond.

Then again, the idiots that have challeged its use are probably the same nitwits that ignore vast swaths of evidence against abstinance only programs, in favor of forcing them as the “suggested” policy too. People can be idiots. Self absorbed religious BS that distorts the truth and denies reality **guarentees** idiocy. And there are 10 million Kent Hovinds (who either believe in lying if it “seems” like the lie supports what the Bible says) for every one St. Thomas Aquinas (Who stated that the only thing worse than an unbeliever attacking a religion they didn’t know anything about was a believer making a fool out of religion by denying reality, in favor of long held, but provably superstitious, bullshit). Thus: Cure for addiction that gets you high = Never. Endless war against people that keep inventing more and more destructive drugs, with no cure *at all* for any of it and no consistent attempt to help them = Righteous.

Just one of the insane things about the other sides strange and warped view of reality that disgusts and disturbs me…
#4 Mustafa Mond, FCD
January 1, 2007

Booty, Jarrett key USC’s 32-18 romp over Michigan
#5 darius
January 2, 2007

My guess is that if an easy way to administer the stimulants is found, they will shortly be packaged with narcotics to make them more effective (and to increase profit margins). =]
#6 Shelley Batts
January 2, 2007

Yeah, my general feeling is that the more is known about the pathways involved in drug addiction, the better that knowledge can be utilized—for better or for worse. Drug companies may find ways to use agonists or antagonists to the pathway’s receptors to lessen the pain or withdrawl or to increase the analgesia produced by a painkiller. However, like darius mentioned, it may also be used by enterprising dealers to increase the potency of the high (and perhaps the speed of addiction). This has already happened in the Detroit area with dealers adding fentanyl to heroin to produce a stronger high.
#7 daksya
January 2, 2007

Haven’t you folks heard about co-administration of opioid antagonist (which implicates ‘aberrant Gs signalling’ as responsible for tolerance?

Here:

Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor-G protein coupling and Gbetagamma signaling.

Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low back pain. (Phase III trial)

Obviation of opioid withdrawal syndrome by concomitant administration of naltrexone in microgram doses: two psychonautic bioassays.

More here.

Also, the common perception that chronic opioid use results in diminished effect seems to be wrong. See

Pleasure into pain: the consequences of long-term opioid use.
#8 daksya
January 2, 2007

Consider this: In the 1950s, a scientist named Wikler conducted an experiment to measure the intake of morphine of a addict who was given free access over 100 days (clearly this could not be repeated today!). He found that addicts increased their drug intake from around 50mg in the beginning, to over 1400mg after 100 days!

I should respond to this as well. You should also consider the pioneering controlled psychopharmacology experiments by Beecher where groups of 20 (with 20 controls) were given injections of amphetamine, heroin, morphine.. to evaluate subjective effects and it was found that 6 (of 20) subjects in the placebo group reported euphoria; 9 in the heroin group; 14 in the amphetamine group. Between 6-8 (don’t remember exact number now) in the heroin group reported dysphoria(!!), compared with none in the AMPH or placebo group.
#9 ivan
January 2, 2007

The end of the experiment from 1950s must had been a hell for the poor addict. Sounds so miserable to be back to reality again.
#10 L
January 3, 2007

Are addicts “addicted because they need more” or do they “need more because they are addicted”?

If a drug user does not does not develop a tolerance over time and threfore does not need more drug to get the same high, does that mean that they are not an addict?
#11 daksya
January 3, 2007

If a drug user does not does not develop a tolerance over time and threfore does not need more drug to get the same high, does that mean that they are not an addict?

The formal definition of addiction is a compulsive drive of drug-seeking i.e. a type of physical or mental behavior rather than state. Dependence, OTOH, is habituation. Now various lines of research in the past decade have shown that negative reinforcement (alleviating negative affect due to drugs cessation) is a larger proponent of addiction than previously attributed. Hence, one can be an addict without being physically dependent, but that’s less likely than if one is, which will be the case if you develop tolerance. Consistent with that assertion, research has shown that cocaine users who develop tolerance are more likely to become addicted than those who don’t.
#12 ivan
January 3, 2007

Both the development of tolerance and addiction are results of brain-plasticity processes that take place. Somehow it seems logical that the addiction happens more easily in individuals whose reward pathways are already under rearrangement as the tolerance is developing.
#13 L
January 4, 2007

“The formal definition of addiction is a compulsive drive of drug-seeking i.e. a type of physical or mental behavior rather than state.”

“Both the development of tolerance and addiction are results of brain-plasticity processes that take place.”

I’m confused.

“brain-plasticity processes” — or at least the outcome thereof — sounds like “states” to me.

Besides, aren’all human behaviors the result of brain states? (this is not an invitation to discuss religion, by the way)
#14 ivan
January 4, 2007

If you would explain what makes you confused, maybe I would have easier time clarifying what I said. Basically, brain homeostasis is disturbed once the brain gets repeatedly exposed to drug of addiction. Development of tolerance is off course underlied by some brain-plasticity process taking place, as well as the development of addiction. My point is that once the homeostasis is disturbed, the opportunity for these processes to take place is there. Addiction is a state, but the path leading to addiction is a process, I guess.