Reward and Punish: Say Hello to Dopamine’s Leetle Friend

  Dopamine recruits a helper to track drug rewards.

Ah, dopamine. Whenever it seems like researchers have finally gotten a bead on how that tricky molecule modulates pleasure and reward, and the role it plays in the process of drug and alcohol addiction, along come new findings that rearrange its role, deepening and complicating our understanding of brain function.

We know that the ultimate site of dopamine activity caused by drugs is the ventral tegmental area, or VTA, and an associated structure, the nucleus accumbens. But dopamine neurons in the VTA actually perform two distinct functions. They discriminate acutely between the expectation of reward, and the actual reward itself. Pavlov showed how these dual functions are linked, but the manner in which dopamine neurons computed and then dealt with the differences between expectation and reward—a controversial concept known as reward prediction error—was not well understood.

We all know about reward and punishment, however. Years ago, behaviorism’s emphasis on positive and negative reinforcement demonstrated the strong connection between reward, punishment, and learning. As Michael Bozarth wrote in “Pleasure Systems in the Brain,” addictive drugs “pharmacologically activate brain reward mechanisms involved in the control of normal behavior. Thus, addictive drugs may be used as tools to study brain mechanisms involved in normal motivational and reward processes.”

But how does the evolutionary pursuit of pleasure or avoidance of punishment that guarantees the survival of an organism—fighting, fleeing, feeding, and… fornicating, in the well-known “4-F” configuration—become a pathological reversal of this function? To begin with, as Bozarth writes, “the direct chemical activation of these reward pathways does not in itself represent any severe departure from the normal control reward systems exert over behavior…. Simple activation of brain reward systems does not constitute addiction!”

What does, then? Bozarth believes addiction results from “motivational toxicity,” defined as deterioration in the “ability of normal rewards to govern behavior.” In an impaired reward system, “natural” rewards don’t alter dopamine function as strongly as drug rewards. “Direct pharmacological activation of a reward system dominates the organism’s motivational hierarchy at the expense of other rewards that promote survival,” Bozarth writes. The result? Drug addicts who prefer, say, methamphetamine to food.

How does an addict’s mind become so addled that the next hit takes precedence over the next meal? A group of Harvard-based researchers, writing in Nature, thinks it may have a handle on how the brain calculates reward expectations, and how those calculations go awry in the case of heavy drug and alcohol use.

The dopamine system somehow calculates the results of both failed and fulfilled expectations of reward, and uses that data in future situations. Cellular biologists, with some exceptions, believe that dopamine neurons effectively signal some rather complicated discrepancies between expected and actual rewards. Dopaminergic neurons were, in effect, computing reward prediction error, according to the theory. They were encoding expectation, which spiked when the reward was better than expected, and fell when the reward was less than expected. As Scicurious wrote at her blog, Neurotic Physiology “If you can’t predict where and when you’re going to get food, shelter, or sex in response to specific stimuli, you’re going to be a very hungry, chilly and undersexed organism.” (See her excellent and very readable post on dopamine and reward prediction HERE. )

But nobody knew how this calculation was performed at the cellular level.

Enter research mice.

As it turns out, dopamine is not the whole story. (A single neurotransmitter rarely is.) Dopaminergic neurons account for only about 55-65% of total neurons on the VTA. The rest? Mostly neurons for GABA, the inhibitory transmitter. “Many addictive drugs inhibit VTA GABAergic neurons,” the researchers note, “which increases dopamine release (called disinhibition), a potential mechanism for reinforcing the effects of these drugs.” By inhibiting the inhibitor, so to speak, addictive drugs increase the dopamine buzz factor.

The researchers used two strains of genetically altered mice, one optimized for measuring dopamine, the other for measuring GABA. The scientists conditioned mice using odor cues, and offered four possible outcomes: big reward, small reward, nothing, or punishment (puff of air to the animal’s face). Throughout the conditioning and testing, the researchers recorded the activity of neurons in the ventral tegmental area. They found plenty of neurons with atypical firing patterns. These neurons, in response to reward-predicting odors, showed “persistent excitation” during the delay before the reward. Others showed “persistent inhibition” to reward-predicting odors.

It took a good deal of sorting out, and conclusions are still tentative, but eventually the investigators believed that VTA dopamine neurons managed to detect the discrepancy between expected and actual outcomes by recruiting GABA neurons to aid in the dendritic computation. This mechanism may play a critical role in optimal learning, the researchers argue.

Furthermore, the authors believe that “inhibition of GABAergic neurons by addictive drugs could lead to sustained reward prediction error even after the learned effects of drug intake are well established.” Because alcohol and other addictive drugs disrupt GABA levels in the brain’s reward circuitry, the mechanism for evaluating expectation and reward is compromised. GABA, dopamine’s partner in the enterprise, isn’t contributing properly. The ability to learn from experience and to accurately gauge the likelihood of reward, so famously compromised in active addiction, may be the result of this GABA disruption.

Naoshige Uchida, associate professor of molecular and cellular biology at Harvard, and one of the authors of the Nature paper, said in a press release that until now, “no one knew how these GABA neurons were involved in the reward and punishment cycle. What we believe is happening is that they are inhibiting the dopamine neurons, so the two are working together to make the reward error computation.” Apparently, the firing of dopamine neurons in the VTA signals an unexpected reward—but the firing of GABA neurons signals an expected reward. Working together, GABA neurons aid dopamine neurons in calculating reward prediction error.

In other words, if you inhibit GABA neurons through heavy drug use, you screw up a very intricate dopamine feedback loop. When faced with a reward prediction error, such as drug tolerance—a good example of reward not meeting expectations—addicts will continue taking the drug. This seems nonsensical. If the drug no longer works to produce pleasure like it used to do, then why continue to take it? It may be because dopamine-active brain circuits are no longer accurately computing reward prediction errors. Not even close. The research suggests that an addict’s brain no longer registers negative responses to drugs as reward errors. Instead, all that remains is the reinforcing signals from the dopamine neurons: Get more drugs.

[Tip of the hat to Eric Barker (@bakadesuyo) for bringing this study to my attention.]

Cohen, J., Haesler, S., Vong, L., Lowell, B., & Uchida, N. (2012). Neuron-type-specific signals for reward and punishment in the ventral tegmental area Nature DOI: 10.1038/nature10754

Photo Credit: http://www.zazzle.com 

Heroin in Vietnam: The Robins Study Reexamined

How everything we knew about heroin was wrong.

Editor's note: The famous Robins study on heroin use among Vietnam veterans has been so often—and so recently—misinterpreted that I felt motivated to reprint an older post on the subject.

[Originally posted 7/24/10]

In 1971, under the direction of Dr. Jerome Jaffe of the Special Action Office on Drug Abuse Prevention, Dr. Lee Robins of Washington University in St. Louis undertook an investigation of heroin use among young American servicemen in Vietnam. Nothing about addiction research would ever be quite the same after the Robins study. The results of the Robins investigation turned the official story of heroin completely upside down.

The dirty secret that Robins laid bare was that a staggering number of Vietnam veterans were returning to the U.S. addicted to heroin and morphine. Sources were already reporting a huge trade in opium throughout the U.S. military in Southeast Asia, but it was all mostly rumor until Dr. Robins surveyed a representative sample of enlisted Army men who had left Vietnam in September of 1971—the date at which the U.S. Army began a policy of urine screening. The Robins team interviewed veterans within a year after their return, and again two years later. 

After she had worked up the interviews, Dr. Robins, who died in 2009, found that almost half—45 per cent—had used either opium or heroin at least once during their tour of duty. 11 per cent had tested positive for opiates on the way out of Vietnam. Overall, about 20 per cent reported that they had been addicted to heroin at some point during their term of service overseas.

To put it in the kindest possible light, military brass had vastly underestimated the problem. One out of every five soldiers in Vietnam had logged some time as a junky. As it turned out, soldiers under the age of 21 found it easier to score heroin than to hassle through the military’s alcohol restrictions. The “gateway drug hypothesis” didn’t seem to function overseas. In the United States, the typical progression was assumed to be from “soft” drugs (alcohol, cigarettes, and marijuana) to the “hard” category of cocaine, amphetamine, and heroin. In Vietnam, soldiers who drank heavily almost never used heroin, and the people who used heroin only rarely drank. The mystery of the gateway drug was revealed to be mostly a matter of choice and availability. One way or another, addicts found their way to the gate, and pushed on through. 

“Perhaps our most remarkable finding,” Robins later noted, “was that only 5% of the men who became addicted in Vietnam relapsed within 10 months after return, and only 12% relapsed even briefly within three years.” What accounted for this surprisingly high recovery rate from heroin, thought to be the most addictive drug of all? As is turned out, treatment and/or institutional rehabilitation didn’t make the difference: Heroin addiction treatment was close to nonexistent in the 1970s, anyway. “Most Vietnam addicts were not even detoxified while in service, and only a tiny percentage were treated after return,” Robins reported. It wasn’t solely a matter of easier access, either, since roughly half of those addicted in Vietnam had tried smack at least once after returning home. But very few of them stayed permanently readdicted.

Any way you looked at it, too many soldiers had become addicted, many more than the military brass had predicted. But somehow, the bulk of addicted soldiers toughed their way through it, without formal intervention, after they got home. Most of them kicked the habit. Even the good news, then, took some getting used to. The Robins Study painted a picture of a majority of soldiers kicking it on their own, without formal intervention. For some of them, kicking wasn’t even an issue. They could “chip” the drug at will—they could take it or leave it. And when they came home, they decided to leave it.

However, there was that other cohort, that 5 to 12 per cent of the servicemen in the study, for whom it did not go that way at all. This group of former users could not seem to shake it, except with great difficulty. And when they did, they had a very strong tendency to relapse. Frequently, they could not shake it at all, and rarely could they shake it for good and forever. Readers old enough to remember Vietnam may have seen them at one time or another over the years, on the streets of American cities large and small. Until quite recently, only very seriously addicted people who happened to conflict with the law ended up in non-voluntary treatment programs.

The Robins Study sparked an aggressive public relations debate in the military. Almost half of America’s fighting men in Vietnam had evidently tried opium or heroin at least once, but if the Robins numbers were representative of the population at large, then relatively few people who tried opium or heroin faced any serious risk of long-term addiction. A relative small number of users were not so fortunate, as Robins noted. What was the difference?

Quotes from: Robins, Lee N. (1994). “Lessons from the Vietnam Heroin Experience.” Harvard Mental Health Letter. December.

See also:

Robins, Lee. N. (1993) “Vietnam veterans' rapid recovery from heroin addiction: a fluke or normal expectation?” Addiction. 88(8), 1037 – 1167.

Origins of the Disease Model of Addiction (Part 1) can be found HERE.

Photo Credit:  soldiersupportproject.org

Mike Doughty Talks About “The Book of Drugs”

Former Soul Coughing front man on sobriety and life as a solo artist.

Over the phone, Mike Doughty doesn’t have much to say about his former band, Soul Coughing. When I mention it, he gives out a low growl as a warning. He said it all in The Book of Drugs, and it doesn’t sound like he had much fun. Although the avant-garde rock band created music that was spiky and sneaky and immensely popular, topped off by Doughty’s monotonic but strangely penetrating vocal delivery on such classics as “Super Bon Bon,” “True Dreams of Wichita,” and “Circles,” Doughty was drug-dependent and miserable. Musician pitted against musician, egos battered and bruised, credit taken and not taken—and Doughty busily running the gamut of addictions from Jack Daniels to heroin, with a ton of marijuana in the bargain. 

But that was the 90s. Since then, Doughty has done two things of note—three, if you count teaching himself German. He has crafted an innovative solo career, and he has escaped from a cornucopia of addictions that had almost buried him alive.

It seems almost unfair that a talented singer/songwriter like Doughty should also turn out to be a good writer, but there you have it. The Book of Drugs is informative but not confessional, rock-snarky but tempered with a round of amends. It is also whip-smart and bitterly funny:

--“Lars would go out and get drunk every night, then stumble in, sounding for all the world like he was going around moving absolutely everything in the room a foot to the left.”

--“Currently, in the studio next door, guitar overdubs were being recorded for a Meatloaf record. Meatloaf was not in attendance.”

--“I smoked three packs a day. Ridiculous. It was like a job. I woke up, and began the work of the first pack. It was a repetitive, manly task, like getting up early every day to chop down pine trees.”

--“Weed addicts are along among drug users in that they think their shit is cute.”

--“The unsingable girl yelled at me, ‘You don’t get HIGH, you just get FUCKED UP!”

Told in an episodic, chapter-free style, the book lays the foundations for Doughty’s future by page 3. “My dad’s dad,” he writes, “was the town drunk in Tullos, Louisiana.” Doughty's father was an alcoholic as well. From the outside, the process is unfathomable: Doughty relates what is known as the parable of the jaywalker: “Guy’s really into jaywalking, his friends are all like, ha ha funny, then he gets hit, they figure he’s done, he does it again, this time gets both legs broke, the friends are like, whoa that’s weird, and then he does it again and they’re bewildered, and he does it again, and they abandon him, and he does it again, and he does it again.”

Here's what Doughty had to say last week in our interview:

--You got sober after embarking on your solo career. Did you hit bottom, in the classic AA sense?

The thing that really made me think was when I was actually addicted to alcohol, and I started waking up in the morning with the shakes, and I just had this very logical reaction, which was like, oh, I’m addicted, this is horrible, so I’ll just start drinking first thing in the morning. And that’s when it was like, holy shit, I’m an alcoholic, there’s alcoholism in my family, and it’s not just a "drug thing." It was kind of acceptable to be a heroin addict for me, but it was not acceptable for me to be a morning drunk.

--Was alcohol your drug of choice, or heroin?

Well, I went through about thirty-five different drugs. I was always good at finding drugs. My struggle was to manage it. If I had to call something my drug of choice, it would be heroin, in terms of the thing that killed the most pain effectively. Eventually, when it stopped working, I’d say, okay, well, I’ll just do it on the weekends, or detox for a couple of days, and I’ll smoke a lot of weed and I’ll drink and I’ll do some coke or ecstasy, and then I can be back on the heroin on weekends.”

--What’s your opinion of addiction as a biological disorder—the disease model approach to it?

I don’t really know any addicts that don’t have trauma in their backgrounds. I think, to activate this thing, there is generally pain that needs to be numbed, or trauma that needs to be gotten away from. One of the things about the disease model is that so many people of the non-alky variety are just so indignant about it. I think we should just give it up. It’s maybe not worth the fight over the semantics of it. It’s like, addicts are killing themselves, they’re unable to stop using drugs, I would think that would be more important than what to call it.

--Did you use any anti-craving drugs, or do any medication-assisted recovery?

I was on naltrexone for a while, but I was getting high on everything but opiates at the time, so it was just a way of not using opiates. I was shit-faced drunk, and stoned, so I don’t know what eliminating one specific drug—I don’t what the ultimate effect of that was, because for me, I would just go out and find something else.

--Did you do any formal detox or treatment before you went into the rooms, as AA is often called?

No. I had a couple of prescribing shrinks and they suggested treatment, because I had insurance, but I was like, fuck that, no way. It’s funny, they cover detoxes and rehabs but they don’t cover talk therapy. Most of my struggle to get into the path of non-self destruction was because of a shrink who just nailed me as an addict the moment I met her. Within probably twenty minutes she was like, "you know, there are AA meetings above St. Mark’s Place." And I was so angry, like, "what are you talking about?" So a lot of the struggle, of, you know, am I an addict, or do I just have a problem with a single drug, or are the rooms just a cult, it’s a religion—somehow she got me to keep showing up. I don’t know what kind of hook she put in me, but I was showing up, strung out, falling asleep in the chair, and she kept me coming back week after week. I don’t know what kind of Jedi mind trick she used.

--You’re one of the few performers who have been willing to admit that for a minority of people, marijuana is addictive and has its own characteristic set of withdrawal effects.

Yeah, my basic line is, if you know a thirty-six year-old wake-and-bake guy, that guy is probably a marijuana addict. I don’t know the science, I don’t know shit about withdrawal, the mentality of addiction, but I know plenty of people that were stoned all day. And they kept doing it. But I definitely believe weed should be legal. First of all, it doesn’t make any sense if alcohol is legal. Second, it’s such a dirty weapon in the drug war. And the drug war is a war on the poor.

-- You’re "co-morbid." You're an addict, and you’re diagnosed as bipolar.

I do know that there was a part of it that was relieved tremendously by meds—a very careful construction of a cocktail of meds by a super-smart prescribing shrink. Really being very cautious and gradual about it. But if I’m really messed up about something emotionally, talk therapy has the most immediate effect. Just being in touch with dudes from the rooms, a sponsor, friends, I’m on a gratitude list with a bunch of guys, we email each other every day—that stuff is a lot more effective in the short term.

--As a polydrug addict and an artist who has seen his way through to sobriety, what message what you like to send to people working in the treatment and recovery fields?

You know, advice is not my scene. I lucked into the right kind of treatment. Something I hear over and over again from people is that they end up with the wrong therapist. It’s like a relationship, essentially. I think it would be great if therapists were very upfront about saying, "If I’m not the right person, then let’s find you the right person.”

--“Don’t push against your own weight,” you sing in “Diane.” It got me thinking about how hard it is for addicts to lift themselves by their own bootstraps through sheer willpower.

If you let go, if you just get out of your own damn way, it will be so much easier. David Mamet wrote a book about the theater, and he has this thing about how directors overmanage plays when they direct them. And his metaphor was that when the airplane was being developed, they had this terrible problem with spinouts. All the time, the pilot would lose control of the plane; it would start spinning and spinning, and crash and hit the ground. So they invented the ejector seat, so if you’re having a spinout, you just hit the button and zoom out into the air with a parachute. And they discovered that pretty much immediately when the pilot was out of the plane, the airplane straightened out and righted itself. That’s how it is, you try to control too much shit, you’re more likely to fuck it up.

--So, things are good?

-- I’m stoked to be sober. I’ve got eleven years now. Things are really good, even when they’re bad, like a bad year financially or whatever, it’s like, oh my god, I’m doing really good. As long as I’m loving the work I’m making, and I have an audience, and I can make a living, those are pretty much the only things I really have any control over.

Interview with Howard Shaffer of the Division on Addiction at Cambridge Health Alliance

Defining addiction, making research more transparent, and dealing with the DSM-V

(The “Five-Question Interview” series.)

Like many incredibly busy people, Dr. Howard J. Shaffer, associate professor of psychology at Harvard Medical School, is generous with his time. This paradox works to the advantage of Addiction Inbox readers, as Dr. Shaffer, the director of the Division on Addiction at the Cambridge Health Alliance, a Harvard Medical School teaching affiliate, has graciously consented to be the next participant in our “Five-Question Interview” series. In addition to maintaining a private practice, Dr. Shaffer has been a principal or co-principal investigator on a wide variety of research projects related to addiction, including the Harvard Project on Gambling and Health, and a federal research project focusing on psychiatric co-morbidity among multiple DUI offenders. He is the past editor of the Journal of Gambling Studies and the Psychology of Addictive Behaviors.


1. Addiction is not like most medical/mental disorders. If you have cancer or schizophrenia, for example, you can’t recover by abstaining from certain things. What’s your response to those who say that the disease model of addiction is misleading?

We should remember that the concept of disease is difficult to define. This makes deciding whether addiction is a disease most difficult. However, I think most people accept the idea that addiction reflects a kind of dis-ease. Whenever people get into this disease model debate, it’s useful to remember that most models of addiction are misleading, and the disease model is no exception. The map is not the territory, the menu is not the meal, and the diagnosis is not the disorder.

Scientific models are simplified representations of complex phenomena. Models of addiction focus our attention to certain features of addiction and blind us to other potentially important aspects of the disorder.1 For example, the moral model of addiction suggested that bad judgment was the cause and piety was the solution. Some neurobiological models of addiction suggest that molecular activity is the cause and medication is the solution. Both of these views are simplifications.

Rather than trying to fit addiction into a particular box, I prefer to think of addiction as a complex multidimensional syndrome – with interactive biological, psychological, and social causes. In this way addiction is similar to other medical, mental and behavioral disorders than we previously have considered. My colleagues and I have been developing a syndrome model of addiction 2-4 that suggests people are vulnerable because of biological, psychological and social influences. When vulnerable people are exposed to a social context that reliably and robustly shifts their subjective state in a desirable direction, they are at the highest risk for developing addiction. What I like about this kind of model is that it holds the potential to help us determine who is at most risk so that we can predict the development of addiction – just like we can predict who is at risk for cardiovascular and other diseases. This kind of etiological model will help us establish primary and secondary prevention programs that can reduce the onset of addiction.

2. You have a book coming out soon about problem gambling and how it can be managed. Is gambling a legitimate addiction?

Gambling, as well as most other behavior patterns, can become excessive, lead to adverse consequences, and squeeze out many previously important and healthy behavior patterns. 5,6 Some behavior patterns like eating broccoli rarely lead to addiction, but other improbable behaviors like listening to music, or playing video games might.

I don’t think about the idea of a “legitimate” addiction anymore, though I used to. Now I think about addiction as a unitary disorder that has a variety of expressions. For example, AIDS is a syndrome with many different expressions. Syndromes like AIDS and addiction are complex because not all of the signs and symptoms associated with the disorder are present all of the time. Gambling addiction is more rare than alcohol dependence. However, the characteristics of different expressions of addiction and the sequelae across sufferers are more similar than different. Further, the treatments – including the medications – that are effective with one expression of addiction often work with another expression. Scientific evidence suggests that behaviors, such as excessive gambling, and substance use, such as cocaine, have similar effects on the neurocircuitry of reward – how the brain processes information to produce the experience of pleasure.

For a pattern of behavior, whether substance involved or not, to be considered as an addiction, it must reliably and robustly shift subjective experience in a desirable direction, lead to adverse consequences, and be associated with identifiable underlying biological and psychological features, for example, genetic influences and trauma.

3. You host the Transparency Project. What is it and why did you create it?

The Transparency Project is the world’s first data repository for addiction-related industry-funded research. Most people don’t realize that private industry funds the majority of scientific research. This particular funding stream is important. However, tobacco industry funded research properly encouraged people to worry that private funding can adversely influence research. In fact, I think observers should worry about the potential bias that might accompany any research, including research supported by public funding sources. There is no warranty that can assure unbiased research, except sound methods and careful data analysis reflecting sound scientific principles. Furthermore, critics shouldn’t presume that research is biased just because it has a particular kind of funding source. We are encouraging scientists who have received industry funding to send their data to the Transparency Project so that others can download and use their data. This should magnify the value of the data by having others analyze it similarly or differently from the original research. This strategy also should help observers both confirm and question findings, thereby leading to important dialogues about the central issues that are so very important to the advance of scientific knowledge.

4. What’s going on right now at the Division on Addiction that you are particularly excited about?

During 2012, we are celebrating our 20th anniversary at the Division on Addiction. The syndrome model is emerging as an important conceptual guide to our work going forward; we are very excited to see that others are similarly interested in this perspective. Very soon, for example, the American Psychological Association will be releasing another of our new books, the APA Addiction Syndrome Handbook. I am also very excited about our DUI research 7-11 as well as our efforts to develop new technology that will help lay interviewers—those often staffing DUI treatment programs—to assess complex psychiatric disorders and triage patients into the care they so desperately need. This is our Computer Assessment and Referral System or CARS project. Lots of people around the world are expressing interest in coming to the Division to study and conduct research focusing on addiction. For me, it is very satisfying to see young people come to the field of addiction with a sense of curiosity, wonder and scientific rigor that have not always been present in this area of interest.


5. How do you feel about the proposed DSM-V changes regarding addiction?

By now, most people interested in addiction are aware that the American Psychiatric Association has expressed some interest in moving Pathological Gambling from the impulse control disorder category to a new Addiction and Related Disorders category. This would represent the first time that the term “addiction” appears in the DSM. If this happens, it is a big deal and, in my opinion, represents a step forward. In many ways it reflects a syndrome model perspective toward addiction. Although pathological gambling has clinical, epidemiological, etiological, physiological, and treatment commonalities with substance use disorders, my colleague Ryan Martin and I have noted that these similarities also exist among the substance use disorders and a variety of other behavioral expressions of addiction (e.g., excessive shopping). A relatively large literature evidences these commonalities. Consequently, we think that the DSM-V work group should avoid creating a long list of addictions and related disorders/diagnoses organized by the objects of addiction. Instead, the syndrome model of addiction encourages an addiction diagnosis that is independent of the objects of addiction, other than as a clinical feature. Diagnostic systems need to identify the core features of addiction and then illustrate these with substance-related and behavioral expressions of this diagnostic class. Conceptualizing addiction this way avoids the incorrect view that the object causes the addiction and shifts the diagnostic focus more sharply toward patient needs.

References

1. Kuhn TS. The structure of scientific revolutions. Second ed. Chicago: University of Chicago Press; 1970.
2. Shaffer HJ, LaPlante DA, LaBrie RA, Kidman RC, Donato AN, Stanton MV. Toward a syndrome model of addiction: multiple expressions, common etiology. Harvard Review of Psychiatry 2004;12:367-74.
3. Shaffer HJ, LaPlante DA, Nelson SE, eds. The APA Addiction Syndrome Handbook. Washington, D.C.: American Psychological Association Press; in press.
4. Shaffer HJ, LaPlante DA, Nelson SE, eds. The APA Addiction Syndrome Handbook. Washington, D.C.: American Psychological Association Press; in press.
5. Shaffer HJ, Martin R. Disordered Gambling: Etiology, Trajectory, and Clinical Considerations. Annual Review of Clinical Psychology 2011;7:483-510.
6. Shaffer HJ, Korn DA. Gambling and related mental disorders: a public health analysis. In: Fielding JE, Brownson RC, Starfield B, eds. Annual Review of Public Health. Palo Alto: Annual Reviews, Inc.; 2002:171-212.
7. Albanese MJ, Nelson SE, Peller AJ, Shaffer HJ. Bipolar disorder as a risk factor for repeat DUI behavior. Journal of Affective Disorders in press.
8. LaPlante DA, Nelson SE, Odegaard SS, LaBrie RA, Shaffer HJ. Substance and psychiatric disorders among men and women repeat driving under the influence: offenders who accept a treatment-sentencing option. Journal of Studies on Alcohol and Drugs 2008;69:209-17.
9. Nelson SE, Laplante DA, Peller A, Labrie RA, Caro G, Shaffer HJ. Implementation of a Computerized Psychiatric Assessment Tool at a DUI Treatment Facility: A Case Example. Administration and Policy in Mental Health and Mental Health Services Research 2007;34:489-93.
10. Peller AJ, Najavits LM, Nelson SE, LaBrie RA, Shaffer HJ. PTSD Among a Treatment Sample of Repeat DUI Offenders. Journal of Traumatic Stress in press.
11. Shaffer HJ, Nelson SE, Laplante DA, Labrie RA, Albanese M, Caro G. The epidemiology of psychiatric disorders among repeat DUI offenders accepting a treatment-sentencing option. Journal of Clinical and Consulting Psychology 2007;75:795-804.

Brain Scans and Addiction Research: The Early Years

X-ray specs for drug effects.

The science of addiction and the technology of brain scans have both developed exponentially in the past two decades. The search for specific neurobiological markers for addiction was made possible by positron emission tomography, better known as the PET scan. Known more casually as the PET/CT scanner, the device was named the Invention of the Year in 2000 by Time Magazine. (The CT scan, for computerized tomography, uses an X-ray machine and a contrast die to measure absorption rates in different brain areas.)

The idea of a PET scan is simple: Doctors inject test subjects with radioactively tagged glucose, which passes the blood-brain barrier with ease. The more electrochemically active portions of the brain burn extra glucose for energy. So, by noting precisely where the tagged glucose has gone, and converting that information into a digital two-dimensional array, a PET scan serves as a neurobiological map of brain activity in response to specific stimuli. Functionally, PET scans are admittedly imperfect pictures of the brain, showing general areas that “light up” during the performance of a task, or in response to a drug. Technically, a PET scanner is detecting gamma rays given off when particles from the radioactive tracer collide with electrons in the brain. A variation on this approach is the SPECT scan (single photon emission tomography).

The neuroimaging techniques that followed, like nuclear magnetic resonance imaging, or MRI, provided an additional level of analysis. MRI machines look similar to PET scanners, but are essentially large magnetic field generators. They were originally known as NMRIs, for nuclear magnetic resonance imagers, but the “nuclear” part seems to have disappeared over the years. MRI scans don’t involve radioactive tracers—they track blood flow, often by means of a contrast agent. Hydrogen, a major component of water and blood, gives off identifiable energy signatures when surrounded by giant magnets. If an area of the brain is showing increased activity, it means that somewhere in that area, some brain cells are demanding more oxygen.  A rush of blood to that area supplies it, an MRI scan detects it, and a computer plots it.

 With PET and MRI scans, scientists could study the brain as a set of molecules in motion. They could create a three-dimensional picture of the brain, with the sagittal, transaxial and coronal planes all visible at once—almost a brain hologram. Addiction scientists could watch tiny areas of the brain light up with activity under the influence of specific mood-altering chemicals. Two areas of the brain were of particular interest. One was the nucleus accumbens, which was involved in the regulation of dopamine and serotonin synthesis. The other was the locus ceruleus—a tiny area of the brain saturated with cells involved in the production and release of the neurotransmitter norepinephrine.

Alcohol, cocaine, the opiates, and other drugs made the nucleus accumbens and associated regions bloom with activity on the MRI and PET scans. These early snapshots of your brain on drugs specifically showed that psychoactive drugs of abuse, the ones that altered mood and emotion, did so at the very sites in the brain known to be involved in regulating emotional states and primary drives. Without scans, scientists would not have been able to confirm the workings of the brain’s reward system in specific anatomical detail.

 As a rule, the same areas of the brain tended to light up no matter what addictive drug was under study. Whether it was a molecule of stimulation, or a molecule of sedation, sooner or later it went surging through the diffuse aggregation of mid-brain structures involved with emotion, memory, mood, sleep, and a host of specific behaviors ranging from appetite to risk-taking.

That the subjects also showed similar brain activity when they quit doing drugs was of equal interest in the beginning. Early work by Dr. Kenneth Blum at the University of Texas Health Science Center and others demonstrated that certain characteristic forms of brain activity took place in the locus ceruleus whenever abstinent addicts experienced strong cravings. The locus ceruleus helps control levels of the original “fight or flight” chemical, norepinephrine, and when an addict in withdrawal panics, the locus ceruleus lights up. Other studies of the nucleus accumbens showed abnormal firing rates in scanned addicts who were deep into an episode of craving. Drug hunger in abstinent addicts, it appeared, was not all in the head, or strictly psychological. Cravings have a biological basis, and brain scans helped to clinch the case.

Graphics credit: http://learn.genetics.utah.edu

A Drug for Head Lice and Heartworm Shows Promise Against Alcohol Abuse

Unlikely candidate helps alcohol-dependent mice cut back on the sauce.

Say what you will about glutamate-gated chloride channels in the parasitic nematode Haemonchus contortus—but the one thing you probably wouldn’t say about the cellular channels in parasitic worms is that a drug capable of activating them may prove useful in the treatment of alcoholism and other addictions.

When scientists go looking for drugs to use against addiction, they do not typically begin with a class of drugs that includes a medication for use against head lice and ticks. But that is exactly where the trail led Daryl Davies, co-director of the Alcohol and Brain Research Laboratory at the University of Southern California. Davies and his group were interested in a set of molecules in the brain known as P2X receptors. A subtype of these receptors, involved in ion channel gating, cease to function in the presence of ethanol. The researchers found that if you keep flooding the receptor with alcohol, these ion gates shut down permanently—an example of how alcohol abuse can change the brain.

Another compound that works on the same ion gate is ivermectin, an anti-parasitic medicine used around the world in humans and animals. As it turns out, ivermectin blocks the effect that alcohol has on P2X receptor subtypes. In recent research, the USC team demonstrated that alcohol-dependent mice drank half as much when they were also given ivermectin. This “newly identified alcohol pocket” is a mystery at present. But ivermectin does appear to work primarily on glutamate systems. (See previous post). For now, the researchers can’t say for certain why ivermectin makes mice drink less, but suspect it has something to do with how the brain signals that it’s time to stop drinking. Davies has speculated that a drug like ivermectin could be of use in treatment programs other than “abstinence-based models.” As Suzanne Wu reports in USC Trojan magazine, the team is now at work on other drugs based on ivermectin’s molecular structure. “If there was already a drug that was 95 percent effective, I might not be studying ivermectin,” Davies told the magazine. “I might not even be in the alcohol field. The funding for alcoholism research hasn’t caught up with the magnitude of the consequences of not finding a cure.”

Photo credit: http://www.usapetexpress.com

A Few Words About Glutamate

Meet another major player in the biology of addiction.

The workhorse neurotransmitter glutamate, made from glutamine, the brain’s most abundant amino acid, has always been a tempting target for new drug development. Drugs that play off receptors for glutamate are already available, and more are in the pipeline. Drug companies have been working on new glutamate-modulating antianxiety drugs, and a glutamate-active drug called acamprosate, which works by occupying sites on glutamate (NMDA) receptors, has found limited use as a drug for alcohol withdrawal after dozens of clinical trials.

Glutamine detoxifies ammonia and combats hypoglycemia, among other things. It is also involved in carrying messages to brain regions involved with memory and learning. An excess of glutamine can cause neural damage and cell death, and it is a prime culprit in ALS, known as Lou Gehrig’s disease. In sodium salt form, as pictured---> it is monosodium glutamate, a potent food additive. About half of the brain’s neurons are glutamate-generating neurons. Glutamate receptors are dense in the prefrontal cortex, indicating an involvement with higher thought processes like reasoning and risk assessment. Drugs that boost glutamate levels in the brain can cause seizures. Glutamate does most of the damage when people have strokes.

The receptor for glutamate is called the N-methyl-D-aspartate (NMDA) receptor. Unfortunately, NMDA antagonists, which might have proven to be potent anti-craving drugs, cannot be used because they induce psychosis. (Dissociative drugs like PCP and ketamine are glutamate antagonists.) Dextromethorphan, the compound found in cough medicines like Robitussin and Romilar, is also a weak glutamate inhibitor. In overdose, it can induce psychotic states similar to those produced by PCP and ketamine. Ely Lilly and others have looked into glutamate-modulating antianxiety drugs, which might also serve as effective anti-craving medications for abstinent drug and alcohol addicts.

As Jason Socrates Bardi at the Scripps Research Institute writes: "Consumption of even small amounts of alcohol increases the amount of dopamine in the nucleus accumbens area of the brain—one of the so-called ‘reward centers.’ However, it is most likely that the GABA and glutamate receptors in some of the reward centers of the basal forebrain—particularly the nucleus accumbens and the amygdala—create a system of positive reinforcement.”

Glutamate receptors, then, are the “hidden” receptors that compliment dopamine and serotonin to produce the classic “buzz” of alcohol, and to varying degrees, other addictive drugs as well. Glutamate receptors in the hippocampus may also be involved in the memory of the buzz.


Writing in The Scientist in 2002, Tom Hollon made the argument that “glutamate's role in cocaine dependence is even more central than dopamine's.” Knockout mice lacking the glutamate receptor mGluR5, engineered at GlaxoSmithKline, proved indifferent to cocaine in a study published in Nature.

In an article for Neuropsychology in 2009, Peter Kalivas of the Medical University of South Carolina and coworkers further refined the notion of glutamine-related addictive triggers: "Cortico-striatal glutamate transmission has been implicated in both the initiation and expression of addiction related behaviors, such as locomotor sensitization and drug-seeking," Kalivas writes. "While glutamate transmission onto dopamine cells in the ventral tegmental area undergoes transient plasticity important for establishing addiction-related behaviors, glutamatergic plasticity in the nucleus accumbens is critical for the expression of these behaviors."

The same year, in Nature Reviews: Neuroscience, Kalivas laid out his “glutamate homeostasis hypothesis of addiction.”

A failure of the prefrontal cortex to control drug-seeking behaviors can be linked to an enduring imbalance between synaptic and non-synaptic glutamate, termed glutamate homeostasis. The imbalance in glutamate homeostasis engenders changes in neuroplasticity that impair communication between the prefrontal cortex and the nucleus accumbens. Some of these pathological changes are amenable to new glutamate- and neuroplasticity-based pharmacotherapies for treating addiction.

This kind of research has at least a chance of leading in the direction of additional candidates for anti-craving drugs, without which many addicts are never going to successfully treat their disease.


Graphics credit: http://cnunitedasia.en.made-in-china.com/