Jesse Lawler: Let's talk about some of the common misconceptions about what dopamine is, what it does. Most people still are thinking of it as the chemical that your brain gives as a reward when you do something correct.

Professor John Salamone:  The pleasure hormone or the pleasure molecules is what people call it. Somehow that idea got into the popular press I mean there are some scientists who have kind of promoted that most scientists who really study dopamine indeed know that or never thought that or always knew it was somewhat oversimplified or have come to realize that it's oversimplified the summary statement that you sometimes hear people say is: "this drug is released when you experience pleasure." In some cases, that's true but that's only part of the story. It's released under other motivational conditions so I think if you step back from it essentially responsiveness to rewarding stimuli is only one class of conditions that dopamine activity is associated with its associated with other things too. There's a distinction between liking and wanting and dopamine doesn't mediate liking but it does mediate wanting. In other words, for example, the behavioural pursuit of motivational stimuli things like that.

Jesse Lawler:  You're actually willing to do something to get what you like.

Professor John Salamone:  Exactly. Drug companies came up with a drug; it's called a dopamine D1 antagonist, Itcopapam, and in the early 2000s it was investigated to try to see if it could block the pleasure from stimulant drugs and so a couple of papers were published a journal called psychopharmacology they gave it to humans and -- I believe it was cocain -- the pleasurable effect the self reported higher euphoria produced from that drug. It's not blocked by these dopamine antagonist there are two publications in that regard in the same year.

There was a paper very recently from a Canadian group -- Marcolaten is this the head of this Canadian group -- and they were looking at cigarette smoking. They had people responding for puffs on the cigarette as a reward. And they also took other various behavioral measures and then what they were able to do...they did a nutritional manipulation to try to blunt dopamine so this is basically the nutritional manipulation if you give people a diet that doesn't contain the amino acids necessary to make dopamine and then you deplete dopamine in the brain. And for example the self reported pleasure or high from cigarette smoking wasn't affected at all and the self reported craving from cigarette smoking wasn't affected at all. But what was affected is working for cigarettes so they had people responding on a progressive ratio schedule where they have to press more and more and more in order to get their puffs of cigarettes that was impaired so that fits again a nice story you, know if you manipulate dopamine systems the main thing you see is not so much an effect on the Donek reactivity or self reported pleasure but rather in things like pursuit of the motivational stimulus.

The more work you have to do the more sensitive you are to interferes dopamine transmission and then what we do is we also developed tests of what is sometimes called effort related choice behavior or effort related decision making in that case what you have is a situation in which you're given a choice, you could have a high effort activity that leads to a larger or a more preferred reward or the other option is a lower effort an activity that leads to smaller or less preferred reward. So we developed these tasks, and what we see again and again is that if you interfere with dopamine transmission particularly in this brain area that was historically linked to pleasure which is the nucleus accumbens. What happens is this: that they still prefer the larger reward versus the smaller reward, but if they have to work harder for the preferred reward then it shifts their behavior so they decrease selection of the high effort activity, But increase selection of the low effort activity

Jesse Lawler:  So the lack of dopamine is this kind of like laziness, essentially.

Professor John Salamone:  Well, yeah. You know I mean to me right. Laziness is closer if you want an approximation: laziness lassitude energy and a lack of energy. Those are closer approximations then and Anedonia lack of pleasure. And so one of the things that's interesting about this is this task has been translated to humans. So there's a researcher named Michael Treadway he developed a human analogue of these effort related choice tasks and he's shown things like if you give a non-pathological person amphetamine, the stimulant drug which increases dopamine transmission that increases selection of the high effort option which is interesting because that's consistent with our view of what happens when you interfere with dopamine. He's also shown that for example people with major depression are more likely to select a low effort options. So in a sense they are biased towards low exertion of effort; now that in itself is an interesting finding because it taps into a whole literature on the symptoms of depression. So depression isn't only about self reporting a negative mood or a dysphoric emotional state, it's also for many people it's about lack of motivation.

Jesse Lawler:  Yea, sort of an unwillingness to do anything about it.

Professor John Salamone:  Exactly. And so having seen that literature emerge, what we've been doing most recently is to try to develop explicit models of some of these motivational symptoms by exploring manipulations that are thought to be associated with depression in humans. So for example one of the things that we've looked at is what are called pro-inflammatory cytokines. So, what are cytokines? They are peptides that are released as a part of your immune response largely a response to infectious disease but they have various motivational effects. So, for example, some pro-inflammatory cytokines are given to people in some cases as treatment, and people report not only depressive symptoms but especially symptoms like an urge a lack of activity, fatigue, those kinds of things. And what it sometimes compares to is something that I think most people have experienced: have you ever noticed when you get an infectious disease, let's say when you first start to get a cold, one of the first things that happens is you feel fatigued and you just sort of feel like "oh, I just want to go home and lay on the couch and put a blanket over myself." So I think a lot of people have experienced this. You know one of the factors that contribute to that is pro-inflammatory cytokines.

So here's an example of how you do essentially a sort of a pre-clinical study: you get a manipulation associated with depression you see if it has the predicted effect which is this effort related to fact in the model. But then you take it one step further you try to reverse that effect by giving a drug that would improve performance. And so we've done that in the case of the pro-inflammatory cytokines.

Another drug we've looked at is a drug called Tetrabenezene. So what does Tetrabenezene do? It basically depletes catecholamines -- so dopamine and norepinephrine -- but it has its greatest effect at low doses of depleting dopamine and it does that because it blocks the storage -- storage mechanisms in nerve cells protect the neurotransmitter from being broken down by enzymes. So storage is a way of keeping stores of dopamine ready for release. Well this drug blocks that storage process so it leads to depletion of dopamine. And why we picked it is because this drug is also associated with depressive symptoms including what is called fatigue. The drug is given for example to Huntington's disease patients but side effects like depression and motivation or symptoms fatigue etc are reported in the literature. So we published a paper a couple of years ago showing that Tetrabenezene induces effort related effects. In other words changes in those procedures that I was describing before: the decreased selection of high effort options.

And then the question is can it be reversed? Can you have a drug that would actually improve motivational performance in a tetrabenezene treated animal. We tried the adenosine A2 antagonist M.S.X.A. and that worked very well. It restored the normal performance across multiple tasks in tetrabenezene treated animals. And then we've also started looking at anti-depressant drugs with various characteristics and this is turned out to be interesting. The first drug we looked at is a drug called bupropion -- the trade name for which is Wellbutrin. So this drug basically increases transmission for dopamine and another neurotransmitter, norepinephrine. How does it do that. It blocks a protein that's called the transporter. So that transport protein -- or the uptake protein it's sometimes called -- is on the nerve terminals and what it does is it removes the neurotransmitter from the synapse, from the synoptic cleft. So it's a way of inactivating the neurotransmitter. Well if you give a drug that blocks that, it leaves more of the transmitter in the extracellular space, so it increases transmission of that particular transmitter. So why we picked that one is because it turns out not all antidepressants seem to work in humans equally well on these motivational symptoms but that was the antidepressant that most of the literature said 'Well if any drug works better, it's this drug.' So we've tried that, and bupropion indeed reverses the effects of tetrabenezene across three of the different tasks that we've actually tested it on. So again you you interfere with effort related functions with tetrabenezene, but you restore the normal pattern of behavior by given you bupropion -- and we publish those papers too.

And now we have some work that's not published yet; I don't mind talking about it, though. So what about S.S.R.I.s for example -- as a group the most commonly used antidepressant drugs. But when you dig into the human literature you find something interesting. It's reported that although S.S.R.I.s like Prozac, for example, or Lexapro, although they improve self reported mood and they reduce anxiety and they reduce rumination -- all important depressive symptoms that they tend to be less effective at treating motivational dysfunction and in fact there are some depressed people who actually have worse motivational function increases in that self reported fatigue an S.S.R.I.s. Interestingly when we tested Prozac (fluoxitine) in our model we did not get an improvement in motivational performance and in fact if anything at high doses it actually made performance worse. So what this told us is something that links into an interesting trend in mental health research; which is to look at individual people in individual symptoms and the individual neural circuits that mediate each symptom rather than lumping everybody together and saying well they're all depressed and depression is kind of this unitary entity instead looking at something like depression from the standpoint of well some people who are depressed gain weight ,some people who are depressed lose weight, some people who are depressed become more agitated or have more anxiety like symptoms. Other people actually have profound psychomotor symptoms that even kind of resemble some of the symptoms of Parkinson's and so not everybody who's depressed is exactly the same.

Not every antidepressant drug works in the same way, nor do they treat each symptom equally. So different drugs seem to work better on the different symptom. This way of looking at psychological disorders is now kind of put under this rubric of what's called the R Doc the research domain criterion approach and this was something that was offered by the NIMH -- the National Institute of Mental Health -- a few years ago. There'd been several publications on it basically trying to promote the idea that researchers should not be locked in by traditional diagnostic categories and think only in that particular way but rather think in terms of specific symptoms in the neural circuits that mediate those symptoms. But what I find is it enables me to understand our area of research better because, for example, if you ask me ‘Well based on your studies of dopamine do you feel that you're modeling depression per se’ and I think ‘You know we're not; what we're doing is we're modeling something that is a feature of depression but it's also a feature of other disorders as well.’ You know we're studying basically a dopaminergic component of that. We're studying the related neural circuitry as well, but it's only a piece of the larger puzzle. In the way I think eventually treatment is going to go in the future is that we will be able to have both better behavioral measures and hopefully neural imaging measures that will enable clinicians to be able to identify types of depressed people, or types of people with other disorders who have a preponderance of a particular set of symptoms and they maybe make recommendations about treatment based on the particular symptoms and the neural circuits involved rather than just sort of blanket treatments based on general diagnostic categories.

Jesse Lawler:  When we think about the motivational problems, depressed people are the first people don't mind was the opposite end of the spectrum would that be like an extreme risk-taker?

Professor John Salamone:  I know what you're saying: I think the classic answer would be people who are manic, who are in the manic phase of bipolar disorder; you know, polar manics, would be the opposite end of that. And they do -- that's one of their characteristics, they do take a lot of risks. Dopamine systems are associated with risky decision making as well as effort related decision making, so I think your point is very good; but in terms of the traditional pathologies I think the manic end of the spectrum tends to be the opposite of what we're describing as just an-urgent depression and people who have bipolar disorder they describe it that way. They report it that way.

Jesse Lawler:  Another thing I want to go back with on your rat studies, and I guess the human studies also, is when you're looking at motivation it all seemed to be the carrot rather than the stick...

Professor John Salamone:  The literature showing that interfering with dopamine and interfering with avoidance performance -- so that's the stick and as you call it -- is actually older than the literature showing that it interferes with positively motivated or positively reinforced behavior. So in fact it was shown many, many years ago when the first anti-psychotic drugs are being developed, that they impair avoidance responding. And so they didn't know it when these early studies were being done, but it turns out they're dopamine antagonists and the interesting finding that was reported -- the classic finding in this area -- is that if you give an animal a dopamine antagonist you interfere with avoidance but not escape. What does that mean? Let's say there's a light that turns on that signals that an aversive or stressful stimulus is going to happen. So avoidance is what happens after you learn that and experience it when the light goes on then you leave. What if the light goes out and you sit there and you wait. But then the aversive stimulus happens and then you move. That's called a escape. So the classic finding was the dopamine antagonist interfered with avoidance but not escape. So yeah the dopamine works with both the carrot and the stick. And then the thing is that even what we just recently have shown is on the positive reinforcement side it doesn't even have to be food reinforced. So the idea of the carrot kind of reminded me of this. So we just developed a procedure in which it's like that...It's the Team A's task -- but it's a different way of doing it. In one arm they choose a running wheel. If you've ever had a rodent pet you know the running wheels are something they will frequently do if given the opportunity; mice do it, rats do it, hamsters do it. So they have a choice between running in a running wheel in one arm versus going to the other arm and drinking a sucrose solution -- so it's like being active or being a couch potato that's there you know and eating the Cheetos on the couch right that's the sucrose solution. And so you know the way we develop the task: animals will choose more so to run on the running wheel; but if you give a dopamine antagonist or give that drug tetrabenezene it depletes dopamine and it shifts their choice behavior it decreases the selection of running in the running wheel but actually increases selection of the sucrose and increases consumption of the sucrose. So essentially the bias that's produced towards low effort activities is not just true of it's a lever pressing for food, it's also true for this activity that kind of in itself is intrinsically reinforcing which is wheel running.

Jesse Lawler:  For people if you're not depressed, they're not manics, they're not necessarily looking for a pharmaceutical solution to management. Are there food precursors that would increase the amount of dopamine that one has readily available in the brain things like that that just might be handy tricks for people to know?

Professor John Salamone:  I think the best thing is to eat a balanced diet from the standpoint of amino acid content. So the amino acids that are most vital are tyrosine for dopamine synthesis and also phenylalanine. So tyrosine is the immediate amino acid precursor of dopamine. So tyrosine is converted in the brain to L.-Dopa which we all know is a drug that's used to treat Parkinson's disease but it's also a molecule that's made in your nervous system. Tyrosine is converted to L.-Dopa. And then L. Dopa is converted into dopamine. Now it turns out, though, that if you didn't have much tyrosine in your diet you could get it another way: you could eat foods that have a lot of phenylalanine and phenylalanine can be converted into tyrosine. So this strikes me because a lot of people, they don't look after how much protein they have if they eat a lot of junk food that doesn't have to happen to have a lot of protein or even a lot of people who eat vegetarian diets -- and for some people a vegetarian diet means doing research and finding out and mixing beans and whole grains and getting the right amino acid content -- for other people a vegetarian diet may mean eating potato chips and a few other things and they're all vegetable so they're fine. You know some people will balk when they hear that but trust me I know individual people who eat that way and I think from the standpoint of synthesizing dopamine it's vital that you don't eat that way and if you're going to have a vegetarian diet you want to do what a lot of vegetarians do they know well, gee, then I need to eat some of this, some of that, some of the other stuff to get that amino acid content to balance things out.

And one of the interesting things I've started to realize too is if a depressed person doesn't eat normally, they could be making their situation worse, because they're not giving themselves the amino acid content that promotes normal neurotransmission. And this is not just true of dopamine, this is true of other neurotransmitters: so serotonin, the amino acid precursor for that is tryptophan. So again eating a diet that includes a reasonable amount of tryptophan is important in terms of maintaining serotonin synthesis. But now there's another thing that's interesting to keep in mind, because some people might think 'Wow, if some tyrosine and phenylalanine is good, then more must be better maybe it must stimulate me.' And the problem with that is, let's just say you are eating a balanced diet you do have a variety of amino acids and it includes tyrosine and phenylalanine; you're maintaining your normal dopamine synthesis, but in fact under normal nutritional conditions, the enzymes that convert for example tyrosine to L. dopa. They're relatively slow. So they are in a state that's called saturated. Meaning what? If you eat more you're not going to synthesize dopamine any faster because you've saturated the enzyme. So sometimes, you know, I think people who are wanting to do nutritional manipulations to manipulate some of these motivational conditions. The rule should be: maintain normal levels, but don't overdo it. Overdoing it probably doesn't do you any good.