Addiction & Learning: More Than Glutamate and Dopamine

“Addiction is a brain disease,” Alan Leshner declared in Science in 1997. Back then it was dopamine the magical molecule that explained destructive substance use (and before that, tolerance…). Dopamine drove craving, dopamine made pleasurable irresistible, dopamine made addicts chase rewards that existed only in warped neural chemistry.

I am drinking a fine Pinot Grigio as I write those words. Sure, the wine and the taste and pleasure can be reduced to brain chemicals. But does that really explain why I bought this bottle, crystalline, on my wife’s first day back to full time work? Does it explain our “cheers” before dinner, and the memories of other Pinot Grigios with my wife? No, of course not. Craving matters, and deeply so in addiction. But it is not the whole story.

A recent article in the NY Times, Lasting Pleasures, Robbed by Drug Abuse, presents the psychiatrist Richard Friedman’s take on this whole phenomenon, leavened with the terrible difficulties of trying to treat addicts and the apparent promises of brain-based explanations.

We understand the initial allure of recreational drugs pretty well. Whether it is cocaine, alcohol, opiates, you name it, drugs rapidly activate the brain’s reward system — a primitive neural circuit buried beneath the cortex — and release dopamine. This neurotransmitter, which is central to pleasure and desire, sends a message to the brain: This is an important experience that is worth remembering…

Even so, the acute pleasure fades when the neurons in the reward circuit get used to all that dopamine. Eventually, as with my patient, even higher and higher doses cease to feel good as users try in vain to recapture the initial high.

So what explains compulsive drug use, especially when it brings the user to the brink of personal ruin?

I got a clue from my patient’s recent relapse. After nearly six months of abstinence, he found himself inexplicably craving cocaine on the way home from work.

It happened that he had run into an old friend just outside his office with whom he had used drugs years earlier. Although he did not consciously associate the friend and the drugs, his brain had not forgotten, and the meeting touched off the urge to use again.

In short, recreational drugs like cocaine don’t just usurp the brain’s reward circuit; they have powerful effects on learning and memory.

Learning and memory become the new explanation. In Friedman’s case, at least in this short essay, his explanations still drew on dopamine.

Though my patient had not used methamphetamine, cocaine has similar effects in the brain. With years of abuse, he could have lost enough dopamine transporters that his own reward circuit would become dulled to everyday pleasures.

But recent research highlights the importance of glutamate, the new neurotransmitter-as-cause explanation. Here’s the Wikipedia take on glutamate:

Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system…. Because of its role in synaptic plasticity, glutamate is involved in cognitive functions like learning and memory in the brain[3]. The form of plasticity known as long-term potentiation takes place at glutamatergic synapses in the hippocampus, neocortex, and other parts of the brain.

Peter Kalivas has been a leader in this area of research. Here is the bare-bones glutamate presentation in Kalivas et al. 2009:

Cortico-striatal glutamate transmission has been implicated in both the initiation and expression of addiction related behaviors, such as locomotor sensitization and drug-seeking. 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.

In a 2007 Nature article Kalivas and O’Brien are more explicit on the learning & memory side, fingering glutamate in the body of the article as the culprit:

Using addictive drugs can evolve from controlled social use into the compulsive relapsing disorder that characterizes addiction. This transition to addiction results from genetic, developmental, and sociological vulnerabilities, combined with pharmacologically induced plasticity in brain circuitry that strengthens learned drug-associated behaviors at the expense of adaptive responding for natural rewards. Advances over the last decade have… contributed to an expanded understanding of how drugs usurp normal learning circuitry to create the pathology of addiction, as evidenced by involuntary activation of reward circuits in response to drug-associated cues and simultaneous reports of drug craving.

Sorry, dopamine, you’ve been a nice causal agent since the early 1990s. Now it’s a dual destiny. Dopamine equals bad craving, glutamate equals bad learning. Or if you’re not in a moral frame of mind, then just say something along the lines of “dopamine and glutamate make up the disease of addiction.”

That’s the easy critique most anthropologists would make. Friedman needs an explanation for what is unexplainable: “Of all the things that people do, few are as puzzling to psychiatrists as compulsive drug use. ” Dopamine and glutamate literally provide him an explanation, and maintain power over the patient as well.

But I believe anthropology can work fruitfully with neuroscience. I’ve embraced and extended the dopamine/craving paradigm in previous research on craving and in calling for the importance of subjectivity in re-thinking the disease model. But dopamine had seemed the easy one. Terry Robinson and Kent Berridge have characterized dopamine as “wanting” – what could be more human than desire?

Now we face glutamate. Will it be like dopamine in the early days, when dopamine was simply equated with reward deficiency, or a lack of pleasure? Low dopamine + missing high = addict.

Now it’s glutamate + problems of learning & memory = addict. Or glutamate + lost neuroplasticity = ingrained bad habits, if you want to put out something more general.

There is nothing wrong with examining the molecular mechanisms behind general psychological/cultural phenomena, where glutamate is a key neurotransmitter linked to addiction and implicated in the basic functioning of learning and memory. And I certainly applaud the move toward a more complex, a richer, view of addiction than just “dopamine made me do it.”

But I’m sorry, “dopamine and glutamate made me do it” is just not very satisfying.

The key for me has been to come back to the basic point. Addiction is not just pleasure and craving. It is also about learning and memory.

In fact, that is just what my long-term research with drug users (and non-users) has shown me in Colombia and the United States. What else is “functional use” than an aspect of learning and memory?

I spent a long time in Colombia exploring learning and memory in relation to drugs and drug use, and with a range of people from adolescents who had never tried, on-going hard users, and recovering substance abusers. I just didn’t phrase it so simply as “learning and memory,” and certainly didn’t talk about glutamate as the way to explain it. (After all, glutamate was just a gleam in a Calvinist, sorry Kalivas’, eye back then…)

To give one example, I was astounded by the regularity in initial statements by all adolescents about alcohol and drugs, where alcohol was inevitably “good and bad” in a repetitive way owing much more to culture than to any loss of neuroplasticity.

At the more extreme end, I gave users the chance to explain statements similar to what Friedman’s patient said, “cocaine doesn’t get me high any more and still I can’t stop.” Drugs, due to ingestion, social context, and pharmacological effect, still produce a potent change in subjective state. Users might not get high, but they certainly get somewhere – and that learned sense of somewhere, where drugs mark the difference that makes a difference, remains deeply alluring to users.

Craving is not only dopamine and unconscious learned associations – it is something addicts want, recall vividly, and share with each other. But it’s not something often shared with those in positions of power, who are quick with their own moral or disease explanations wrapped in biology and generally not well positioned to understand what addicts have actually learned and remember.

Coming back to theory, I explained learning & memory in terms of embodied cognition, cultural models, and social knowledge. It is certainly nice now to be able to tie that more explicitly into some biological mechanisms, principle among them glutamate. But I wouldn’t dare say something like, “his brain had not forgotten.”

HE hasn’t forgotten, the patient, and the meanings of his use, the friends he had, the escape through use, all of these are more than just dopamine and glutamate.

Learning and memory do play a central role in addiction. I’d just rather focus on the learning and the memories. They actually matter to people, and thus offer a profound window into why people use and abuse drugs.

To paraphrase William Shakespeare through Juliet’s lips:

What’s Glutamate? it is nor hand, nor foot,
Nor arm, nor face, nor any other part
Belonging to a man. O, be some other name!
What’s in a name? that which we call a rose
By any other name would smell as sweet

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12 Responses to Addiction & Learning: More Than Glutamate and Dopamine

  1. Oldak says:

    You took down that straw man very skilfully. But then, it’s easy to reduce a position you oppose into something that is easy to argue against.

    When neurobiologists talk about dopamine or glutamate being implicated in this or that behaviour, they are not assigning agency to dopamine or glutamate. This is simply a shorthand way of referring to the neural circuits containing a significant number of cells mediated by dopamine or glutamate. This isn’t to say that the neurotransmitter, or cells and circuits containing the neurotransmitter, act in isolation in mediating a behaviour. It is simply an indication that processing in a particular circuit plays a significant role in a resulting behaviour (here, addiction). This does not preclude environmental memory, or social association, or the brain activities responsible for these, playing a role in the behaviour.

    When you attack a simplified model of a system, you are not attacking the system itself, as others understand it to be.

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  2. Dirk Hanson says:

    All these systems impinge on one another. The trio of primary reward chemicals–serotonin, dopamine, and glutamate (and, yes, maybe others yet to come) affect each other in complex ways, and the specifics of it are very hard to tease out. Combine that with the behavioral aspects, the operations of “environmental memory and social association,” and we have the makings of a very difficult disease entity.

    I think we can all agree at this stage that it is never just one drug, or one gene, or one neurotransmitter, or even one family of neurotransmitters, that governs drug craving in addicts.

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  4. Mike says:

    Don’t forget that dopamine, serotonin are a part of culture as well. Biochemical theories of addiction change the way people use those substances. Many sites online allow people to share their experiences and theories about how drugs affect the mind. Learning about glutamate actually alters how those same receptors are expressed in the brain.

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  5. daniel.lende says:

    A trifecta of comments, right across the neuroanthropological range. Thanks to all.

    Dirk is right in calling addiction a “very difficult disease entity,” and if anything, my post is an attempt at trying to reveal more of those complexities than are often considered.

    In that sense, Oldak, I’ll disagree – I don’t think I am taking down a straw man at all. Leshner and Friedman very much meant what they said, and you can see the current head of NIDA, Nora Volkow, saying similar things in HBO’s Addiction series.

    When they talk the way they do, they literally are assigning agency to dopamine doing this or that. That’s how language works, and that’s also how they explain the ideas to a broader public. So in that I am right along with Mike.

    In their work, the best neuroscientists do what you are saying, Oldak – they understand that they are researching a neural circuit with a significant number of cells mediated by dopamine or glutamate and often trying to figure out the impact of those circuits on other circuits or trying to figure out how the other factors you mention, say environmental memories or social associations, affect the functioning of that particular circuit. And that’s all very solid, and very useful.

    Some problems can arise when people go from their specific domain of study to Dirk’s complex disease entity. That’s a harder nut to crack, and also where interpretation, assumptions, ideas about causation, familiarity with other fields, actual work with people who suffer from the problem, and so forth affect the assertions or theories or hypotheses that researchers put forward.

    One of my main points is that this process can go more smoothly if we recognize that we often assign causal agency where we really shouldn’t (so the start of my comment) and if we draw on substantive research that actually examines the people and the disease – research that I believe anthropology can provide well. Our reasoning about the role of neural circuits takes on more life when we actually understand more about the life of the problem, and not just about which neural circuits are implicated in a particular problem.

    Anyway, thanks for your comments. You’ve already got me thinking about another post I could write…!

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  7. Peter Kalivas says:

    This is very interesting, thanks Daniel for tuning me onto your blog.

    Most of us, even the director of NIDA, understand that neither dopamine nor glutamate explain addiction. Two points to make along these lines, akin to Dirk and Oldak. 1) The day we understand the brain as an organ in reductionist terms, we might be able to provide a tight linear cause and effect analysis from gene to transmitter to circuit to a complex behavior like addiction. That holy grail (reference to Calvin perhaps) is slipping through the fingers of my generation of scientist, it’s a long game. However, I think those of us trying to explain behavior from the bottom up believe that unlike the search for the holy grail, our journey will eventually get us an explanation that is workable in terms of explaining human behavior and curing behavioral pathologies. 2) The reason behind our penchant to build magic molecular bullets to explain complex behavior is simple and political (sounds depressingly like a Tea Party). We are trying to find a pharmacotherapy, and the current FDA-approved state of the art is usually a single molecular target. Do we believe that a single molecule defines a behavior like addiction, of course not. Do interest rates define an economy, no, but adjusting them can fix a problem (perhaps not with the current economy, bad example).

    A final thought on learning and memory, and neuroanthropology. I think that the most accurate and utilitarian understanding of human behavior in our lifetimes will arise from iterative processing between fields like anthropology and neurobiology. Learning and memory is in the gun sights of reductionist experimentation, and we are likely to have some pretty solid molecular/circuitry explanations in 10-20 years (maybe less), perhaps at the level we now understand the heart (literally, not as Shakespeare might think of the heart). However, even a process like learning is little more that an automatic function, largely pre-programmed as a tool to help us navigate. By developing more accurate top-down models of the development and expression of integrated behaviors, an anthropological context gives neurobiologists the framework by which we will design experiments to determine how learning and memory underpins complex behaviors and behavioral pathologies. Conversely, I like to think that our ill-formed certitude of how one or another highly reduced process in the brain influences behavior might help you frame complex behaviors.

    Lastly, Mike perhaps write a blog titled ‘Zen and the Art of Iterative Mental Processing’.

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  10. Rich and Co. says:

    Our understanding, wrong and incomplete of course, is that addiction is:
    - A symptom of inherited DA receptors deficits
    - The DA system is actually mainly a “seeking” system more than a “reward” system
    - Symptomatic of other cortical and deeper system connection impairments, including memory and learning. Short- long-term? Likely both.

    The afflicted brain then can never stop hyper-seeking.

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  11. M. Izabel says:

    Your site is a gem. As a Chef, I am intrigued by glutamic acid, glutamates, and umami. I believe as it is possible to come up with an addictive food, it is also possible to make addictive food less addictive as one of the solutions to fast food-induced obesity. Nutritional anthropologists should look into this. They are the ones I expect to do more lab work than fieldwork in anthropology. Maybe the addictive part of a hamburger is in its beef patty that is rich in glutamic acid and its ions and salts, glutamates.

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  12. Hi Daniel,

    I just found your article. I really like it! You explained everything so well, very simple and clear. I just shared it with a lot of people. You guys have a great blog here!

    Thanks a lot.

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