If you happen to click here and listen to B. B. King sing “The Thrill is Gone,” you might notice that he does not look happy. Nor does he sound happy. And he’s sweating. A lot! He says he’s free, but I somehow doubt it.
What happens when the thrill is gone? That’s a central question for addiction, as most of us know first-hand. In fact, what if the thrill was never there to begin with…?
I said I’d report to you on everything I learned at the conference on behavioral addictions in Budapest last month. First I reported on the common denominator, OCD-type states in brain and behaviour, then I tried to specify the key difference between substance and behavioral addictions, then came Elizabeth’s guest post comparing food and drug addiction, and now here’s Part 4: the genetics of thrill-seeking.
On day 2 of the conference, once my brain was seriously sweating, I met the guy who coined the term Reward Deficiency Syndrome (RDS). His name is Kenneth Blum, and he’s a smallish wiry guy, very intense, seemingly dour, but flashing the occasional dry smile. Here’s his hypothesis:
When we take drugs, or do whatever it is we’re addicted to, the brain systems that “light up” include dopamine circuits in the striatum and its neighbours. No surprise there. Blum lists half a dozen dopamine receptors that get in on the act. But the lead role goes to the D2 receptor — which controls the amount of dopamine available to synapses all over the frontal cortex and striatum. The D2 receptor is involved in attention, motor control, motivation….lots of pretty important stuff. Here’s a detailed description. So what happens when the D2 receptor population isn’t quite normal (e.g., too many or too few)? What happens is that you are more likely to suffer from a whole host of things, including OCD, ADHD, schizophrenia, and — you guessed it: addiction. Addiction to drugs, booze, gambling — that receptor has a lot of connections with the underworld of our psyches.
The problem is that the gene that’s responsible for growing D2 receptors, while we’re in the womb, has got different variants (like many genes), and one of those variants (allele A1) causes an overall reduction in the number of D2 receptors. There’s lots of evidence that addiction runs in 
families, and I’ve usually been reluctant to pin it all on genetics. Why? Because most scientists agree that there’s no single gene or cluster of genes that causes addiction; genetic predictors of addiction usually depend on personality factors, like impulsivity; and there is so much in behaviour and experience that can bridge generations — for example, you hardly need a genetic boost if your dad is an angry drunk and your mom is seriously depressed. But Blum cites some pretty convincing research showing that addictions shared across generations (like father, like son) correspond with this nasty dopamine allele. It shows up in more than one generation! That is to say the allele gets passed down, along with the silverware and the porcelain figures nobody wants.
In a nutshell, some people have fewer D2 receptors, like maybe 40% fewer in some brain areas like the nucleus accumbens. So these people are not as excited about reaching their goals. Their whole “reward system” is relatively flat. Life is not as much of a buzz for them as it is for most people. As with B. B. King, the thrill is gone. In fact, maybe it was never there at all.
If you have the wrong allele of the DRD2 gene, and fewer D2 receptors, and therefore you have RDS, how are you going to get the thrills those around you seem to get? Well, drugs (including alcohol), gambling, and other super-fun stuff might be the most effective way. These “rewards” 
are hyper-exciting for most people. For you, who are chronically under-excited, they might be the only way to feel really engaged with life. At least until you get addicted, which seems like a step backward.
That’s the story, according to Blum. That’s what he talked about in his talk, and that’s what we argued about in the lobby for an hour. Reward deficiency leads you to seek out the biggest bang for your buck. Which makes sense, because everyone wants to feel the excitement that dopamine bestows when something special is about to happen. When I was a kid, about age eight or so, I remember making a disturbing discovery. Almost all the fun I had in life seemed to come with looking forward to things, whether a chocolate bar or a birthday present. Once the desired event was actually happening, it wasn’t as much fun anymore. (I was a weird kid, no doubt.) But for most people, a lot of pleasure comes from anticipation, from approach, and that’s what gets muted with RDS.
By the way, I’m actually working with a guy named Arnt Schellekens here in the Netherlands. He and his team are investigating low dopamine levels as a gateway to alcoholism. So this research direction is pretty close to home.
Despite its appeal, there are some serious problems with the RDS model. I’ll name just two. We know from dozens of studies that drug or alcohol use itself leads to a reduction in dopamine receptor density, or at least dopamine receptor activation, because those receptors tend to burn out or become desensitized when we keep bombarding them with fun stuff. Now that’s getting closer to B. B. King’s complaint: The thrill was there for 
awhile, but now it’s gone. Sound familiar? The question remains: is your dopamine landscape more determined by your genes or by how you use them? Problem #2 is that teenagers as a group are often described in terms of reward deficiency syndrome. Teens can be seen as under-stimulated, probably because the reorganization of the nervous system in adolescence is pretty disorganized. A disorganized reorganization! That would mean that teenage thrill-seeking is not only natural, it’s inevitable, and it serves an important emotional function. Unfortunately, dangerous drugs are often part of the picnic. In other words, genetic contributions to addiction may simply be dwarfed by a tidal wave of thrill-seeking that comes with adolescence.
The jury is still out when it comes to genetic influences on addiction. Few addiction researchers doubt that such influences exist, but their exact mechanisms aren’t well understood. Blum and his colleagues are still chasing down the RDS model, and trying to connect it to other influential models, like Berridge’s incentive sensitization model. There’s a lot to be learned, and I admire researchers like Blum and Schellekens, who keep opening new doors to find out what’s behind them.
Informed by unparalleled neuroscientific insight and written with his usual flare, Marc Lewis’s The Biology of Desire effectively refutes the medical view of addiction as a brain disease. A bracing and informative corrective to the muddle that now characterizes public and professional discourse on this topic.” —Gabor Maté, M.D., author of In The Realm of Hungry Ghosts: Close Encounters With Addiction
It was back in 1996 when I thought i came up with my own diagnosis of what I thought was wrong with me and what led me to live the life I did. I was the class clown, the trouble maker, risk taker, always going out on a limb. My sister and I would say we have a feeling deep inside, that was hard to explain, a void. For me I eventually sought out drugs and alcohol to fill that void. To me it was a lack of reward, it seemed I didn’t get the same reward as others doing the same thing. But at the time I thought it was about my upbringing, like I didn’t get enough pats on the back, enough nurturing as a child. I thought it was the way the brain was wired up, that if you get stimulated to positive things, your brain connects up more to those feelings. But because I was lacking those connections it created a hole that needed to be filled and drugs and alcohol filled that hole.
Sort of parallel to the pre/post synaptic D2 research are the findings that low D2 and/or D3 receptors in the ventral but not the dorsal striatum predicted excalating cocaine use in impulsive animals; and low D2 and/or D3 receptor availability in the dorsal striatum was found in chronic users. I’ve forgotten the source of this, but maybe somone out there in blogland knows.
There’s some ventral-dorsal “shift” literature by the Porrino Lab: http://www.jneurosci.org/content/24/14/3554.full.pdf
There is also some similar work on D2 receptor binding from this group.
Hey, Nicolas and Elizabeth, I charge you (picture a sceptre coming at you, not a pair of cuffs or a credit card… 🙂 …with the mission to go forth and find the relevant references.The ventral-to-dorsal shift is covered by a few studies, e.g., Robbins, but I’ve never heard of whatever it is that Nick is reporting . I’m vaguely grasping that, if you’re impulsive (I am, by the way), then it’s a bit of a let-down to have half your v.s. receptors either dead, missing, or on holiday. Picture coming to a beach town on Cape Cod or Florida to party, and finding that it’s all boarded up for the month. You’d have to bring in a lot more booze (or whatever) to have a minimally good time!
Here’s one from the Robbins group. Jeffrey Dalley has a really good model of impulsivity using the 5-choice serial reaction time task. I feel a bit better about this measure than some of the other tasks (i.e., “sign-tracking” vs. “goal-tracking”). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892797/
does this one work?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892797/
U of T interfaces with my browser, so sometimes the links are automatically directed through the library server. Sorry about that!
Also, here’s an article about D2 plasticity and cocaine intake. Basically, the authors propose that the activation of D2 receptors on medium spiny neurons within the accumbens functions to limit control over drug intake. I cannot get the full article, but it adds to the D2 story!
http://www.nature.com/neuro/journal/v16/n5/full/nn.3369.html?WT.ec_id=NEURO-201305
Marc thanks for the diversion of a bit of BB King in the middle of an otherwise hectic day! Actually, BB is very relevant to this genes discussion: Here is a guy who can’t play and sing at the same time, is clumsy with his fingers, and essentially is limited in technique and even note selection – he is genetically unsuitable to be a great guitarist, but, somehow, he is. He is unlimited by his potential!
While the genes are influential and important, they are not the last word – the great 1997 film Gattaca expresses this concept well. In the model of addiction I use and am refining I see genetic input as a “mass” or “motivator” that can form part of the cumulative whole that will push an individual towards addiction. It may even be a critical component – i.e. without it you may never be an addict – but it is certainly not the only component.
As we have previously discussed, in animal studies we see genetically low D2 availability increased through the elevation of social stature within the troop, and a corresponding drop in cocaine administration. Environment certainly trumps genes in certain circumstances!
Your first criticism of the RDS is perhaps not as big a problem as it seems when we consider that reduced D2 availability is a long-term consequence. The short term goal in early use of “thrill” is obtained, but by the time the “thrill is gone”, the addictive stage has made the drug itself the end.
My problem with most theories of addiction is that they try to explain all addiction in one theory. My experience tells me that many theories are true, but as yet none is THE truth when it comes to explaining this thing we call addiction – it is more than a disease, a choice, a syndrome etc etc. It is addiction, and it will require the integration and acceptance of seemingly diverse and even opposing theories before we get to a complete understanding.
What about the one disease – one pathology rule?
But is it even a disease?
Schizophrenia has many possible disease processes for one pathology. We, at this stage, have not found definitive biological markers for addiction, and if we do, there could be a multitude of courses that lead to the pathology.
To simply say that Hypo-whatever is the pathology that has the symptom of addiction is to miss a whole lot of other things – such as reduced gray matter preceding stimulant addiction.
Very thoughtful, Shaun. So low D2 availability can be a critical condition for the onset of addiction. But, as we’ve discussed, D2 density is not something static. There are genetically proscribed levels, so some of this might run in the family, but levels also vary with changes in social status, as you’ve pointed out. And, as per Chris’s comment, two posts ago, people in high-dominance positions may be super-charged with dopamine. So….we can look at dopamine levels as continuing to change with life experience. Which means that the genetic set points are just one marker along the path. Just like BB King (apparently) overcame his “nature” with some determined “nurture”, we can set and reset the conditions that lead to addiction (or not).
So I completely agree: any “one disease — one pathology” rule just doesn’t make sense when it comes to psychological problems like addiction. People can be depressed for many reasons, psychosis can be triggered by chemistry or experience, and addiction can be an end-point — a Rome — to which many roads lead.
Great post – if this is the problem, what is the solution – drugs? meditation? spiritual seeking? positive addictions?
Um, that’s a bit of a tough question. There are many roads leading to Rome, so there have to be many detours for avoiding Rome. Especially crucial during rush hour.
Reading this brought the work of Stephen Suomi to mind. As you know Marc, he studies Rhesus monkeys and how they fare as a result of being raised by attentive and protective moms or inattentive and neglectful ones. In particular, the males who receive insufficient mothering later on become prone to either binging or simply drinking too much during the monkey happy hour. (It does seem comical to imagine the monkeys tossing back shots but the really are exposed to alcohol as part of the research). Suomi also looks at the genetics of these monkeys and he even switches robust monkeys from strong genetic strains with less attentive moms to see what happens. They still fare badly regardless of their hearty stock. And it is expressed in the alleles, though I can’t say how, not being scientifically trained. I suspect they develop something like the r d s you’re describing. The outcome is behaviour that does not serve male adolescent monkeys well–they have a 50 per cent survival rate during adolescence. The ones who make it through appear to have had the better mothering, with some gene-to-environment benefit, meaning that the genetic endowment is maximized through environmental interaction, during infancy, with moms and others. Marc, I leave it to you to clarify why this is similar to our primate group.
Hi Robin,
Suomi’s monkeys inherit long vs. short alleles of a serotonin transporter gene, if I remember right. Two longs make you quite buffered from stress, two shorts make you hypersensitive, and one of each puts you in the middle of the spectrum. Suomi’s research shows that the hypersensitive monkeys are highly vulnerable to poor mothering, and unless raised by a generous peer group they have all kinds of stress-related problems. The insensitive ones do well no matter how poor the parenting is.
The parallel with dopamine is the gene-environment interaction. Bad genes plus good environment and you should do well. With good genes, you can endure almost any environment and come out ok. The difference is that these two gene-personality patterns work in opposite directions. The sensitivity you get with insufficient serotonin uptake is a liability. But so is the INsensitivity you get with insufficient dopamine receptors…because it leaves you with a gap that craves to be filled — RDS — at least that’s how the theory goes.
The lesson? There are two, actually:
Environment can undo much of the potential harm bestowed by an unlucky genetic hand. And…..not all insensitivities are created equal.
I pick up on the part of Marc’s post about adolescent thrill seeking being quite a natural part of growing up. It’s just that this behaviour can lead to tragedy or destructive addictions.
Having studied Aboriginal culture here in Australia to some extent to see how their youth were helped to grow into adulthood,
I became very clear about the dysfunctional nature of our western society in this area and why we experience so many problems with the behaviour of our youth. That can lead to long time problems that remain with them throughout their lives.
Briefly, as I understand it, young aboriginal boys are taken through the different stages of adolescence by different adult males who teach them the different aspects of becoming a man. They are mentored and cared for during this process which takes years. But in a very strict but compassionate way. There is a fair bit of natural risk taking going on during this process, but it is healthy risk taking. Which strengthens their character and teaches them what they need to know as adult males in all aspects of their lives.
I don’t profess to fully understand their incredibly complex culture and it varies from tribe to tribe. Though in my understanding this is generally how males are brought through adolescence.
I’m sure that it is not a perfect system for raising adolescents, but to my way of thinking it sure beats the hell out of the way we ” care” for our youth through this important growing up period of their lives.
But sadly when we Europeans came to this country we virtually wiped out the Aboriginal culture instead of learning from them. Hence where we are today. I am not advocating that this is how we raise our teenage boys. But there is something very dysfunctional about how we raise and care for our youth. The Aborigines found a way for their society to remain mainly functional for over forty thousand years. The more I study the Aboriginal culture of this country, the more I am in awe of their vastly superior intelligence over our Western culture.
Ps I am not sure how girls were brought through adolescence .
The native peoples in Canada also had a unique culture which the Europeans pretty much managed to wipe out. A developmental psychologist named Michael Chandler was very interested in the mental health of the teens raised in this culture, especially because their suicide rate was extremely high in some tribes and essentially zero in others. What made the difference? he wanted to know.
It turned out that there was one and only one factor that predicted youth suicides. In tribes with strong continuity in rituals and customs, there was no suicide. These tribes still kept their traditional language and their traditional governance system — tribal councils, elders, etc. It seemed these kids had a sense of who they were, based on fitting into a community that had a distinct past, present, and future. For kids from tribes that had lost their language and their customs, who sat around watching TV and ate at McDonald’s, this continuity did not exist. These kids had a very underdeveloped sense of personal identity, and therefore they were much more at risk for drug addiction, alcoholism and suicide.
The main message beamed at parents in the Western world seems to be: kids need to be independent! Leave them alone! In fact, the opposite is what needs highlighting: Kids need connection!
Well, it wasn’t all that long ago in our own western cultures that young men worked alongside their fathers, learning their trade or business, and young women spent ample time learning from their mothers. In fact, my own parents, born in the 1937 and 1942 were raised in families where they weren’t expected to leave until they were married (my mother was an already divorced mother of one (me). Even when my parents (adoptive father) married, they lived with my grandparents until they saved enough for a house. This was in the 1960s.
To be clear, we’re talking about modern practices that are quite recent in origin – mid 20th century. Obviously, for us, this is our whole lifetime, but in the context of broader history…
It sounds like you mean that recent generations in Western society are also lacking a connection with their elders. They also find themselves dislocated, devoid of a coherent narrative of who they are and where they fit in. If so, I agree. And I think the greatest instance of this is the breakdown of traditional religious structures. While many of us may not be fond of mainstream religion, it does/did provide a coherent narrative in which to fit our life stories.
And without such narratives, we are all more prone to addiction and other forms of getting lost.
Great post!
Nowadays all these kids who are getting drugged for whatever reason, ADHD etc, what about them. I wonder of the side-effects of the prescription meds on there effects on the maturing/pre-maturing brain cell/receptors?
Good point. Drugs for ADHD enhance dopamine transmission. They may indeed be messing up receptor densities, with unknown impacts on future addiction problems.
Perhaps the prolonged drug usage flattens out our ability to feel the thrill, not the other way around. Especially during adolescence when our brain is still forming and very gullible to external stimuli, where the search for exciting things rewires our brains to be programmed to enjoy them, using drugs during this period will numb our senses and disallow such rewiring to take place in a normal manner. Therefore, without drugs we cannot enjoy and only with drugs we feel “normal” again because of the false drug-induced kick.