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Behavioral tuners

Juan García Ruiz
January 16th, 2022 · 9 min read
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The Greek word enteron means gut. You know that the gut is that part of the digestive system located between the stomach and the anus where part of the absorption of nutrients from the food we eat takes place. In it we harbor an exuberant bacterial flora, as well as other microorganisms that do us more good than harm. Almost a century ago, an Italian man named Vittorio Erspamer found a molecule (specifically a monoamine) in intestinal cells that was capable of causing intestine contractions. As he was a very creative man, he wanted to give his molecule an original name, and so enteramin was born (yes, enteron and amine, enteramin, the amine of the intestine). What if I told you that you already knew about enteramin before reading this paragraph? A few years later, Arda Green, Irvine Page and Maurice Rapport discovered a molecule in blood serum capable of modifying vascular tone with a vasoconstrictor effect. Being no less original than our Italian friend, they named this molecule serotonin (you guessed it, serum and tone, serotonin). A few years later they realized that enteramin and serotonin were the same molecule. The latter ended up making its way into our lives and that is how we know this neurotransmitter today. I mentioned that serotonin can induce intestinal contractions and vasoconstriction. But wasn’t it the molecule of happiness? I won’t answer to this question, but Philippe will. He will also tell us about the importance of monoamines and share with us his vision of the research.

Philippe de Deurwaerdère is a professor at the University of Bordeaux since 2000, after obtaining a thesis in neuropharmacology in 1997. He did his postdoc in Los Angeles, where he lived for a year and a half (but he didn’t shoot any film, as he clarified). Then he started working as a professor at the University of Bordeaux. He has been working in several laboratories that have helped him evolve, and currently he holds a position at the Institut de Neurosciences Cognitives et Intégratives d’Aquitaine (INCIA).

Juan Garcia Ruiz: Serotonin is often associated with happiness in everyday life. Given its wide distribution in the central and peripheral nervous system, to what extent is it reductive to attribute this unique role to it?

Philippe de Deurwaerdère: I bought toilet paper with a text that read: “dopamine = love” and “serotonin = happiness”. So that’s all it is, it’s just toilet paper. The role of these molecules cannot be reduced to a function. I will paraphrase two of the greats of serotonin, Jacobs and Azmitia: serotonin participates in all functions without being necessary for any of them. It is a neuromodulator. In the periphery, it also modulates organ activity, including the gut (where 80 to 90% of the body’s serotonin is found).

JGR: How can one approach the study of complex neuromodulators such as dopamine or serotonin?

PDD: We have to start from a philosophy of scales. For example, in vitro experiments will allow us to understand the interaction of these molecules with receptors or transporters. This will not explain the function. The scope of a neurotransmitter or neuromodulator can only be pondered through the function of the brain. And what is the function of the brain? The production of behaviors. How does one approach the study of a neurotransmitter system as vast as serotonin? We must never lose sight of this notion of behavior, even if a priori, serotonin itself has little to do with its production. But it is capable of modulating it. It gets very complicated. We can modulate behavior with serotonergic molecules, for example with hallucinogens that target 5HT2A receptors. But these are special cases. Back to the question: how do we do it? We should just not forget behavior, the function of the brain, and the wide distribution of neuromodulators. When we look at the organization of the brain, we realize that serotonin can act in one region and have consequences on the activity of serotonergic neurons projecting to another region. The issue needs to be approached systemically.

JGR: What are the trace amine associated-receptors or Taar1, in a nutshell?

PDD: Trace amines are strange molecules that can be of considerable importance when using molecules such as L-DOPA (editor’s note: L-DOPA is the gold standard treatment for Parkinson’s disease). L-DOPA, a precursor of dopamine, can give rise to other molecules such as tyramine, octopamine, 3-methoxytyramine, 3-methoxytyrosine, 3-O-methyldopa, etc. All these molecules are considered trace amines, and there is a whole family of receptors to which they can bind with high (nanomolar) affinity. Not only trace amines can bind to these receptors. Also molecules like dopamine can do so. So the nomenclature is nice, but one has to be careful with it.

JGR: What does your research consist of?

PDD: This goes back in part to the earlier question about how to approach monoaminergic systems. The fundamental question of my research focuses on understanding the involvement of neuromodulatory systems in the adaptation of organisms. These systems are the key. But it is a strange key. For example, if we suppress the monoaminergic systems in animals, everything seems to be fine. So what they actually do is to allow a better adaptation of the organism to its environment. I use a neurochemical approach, which has the advantage of being quantitative. Even if the amounts of monoamines are completely different from one brain region to another, we can say that these monoamines are there, that they play a role and that they should be studied.

JGR: Why is it so important to study monoamines?

PDD: The study of monoamines is a kind of basic research that allows us to understand the evolution of an organism in its environment. Humans modify this environment. For example, I just saw this new building being constructed on campus. My calculation of space will soon change because of this building. Our modification of the environment has a considerable impact on how we perceive it and how we act. Right now, climate considerations are on the agenda. This issue is almost anxiogenic. So is covid. We have all experienced that post-traumatic stress disorder on a large scale. Facing these situations there are systems that react, usually for the better. We generate certain behaviors, and monoaminergic systems get involved to enhance them, perhaps to the detriment of other behaviors. But when we return more or less to the old normal, it takes us a while to readapt. Or we don’t do it at all. Returning to the old environment can even be potentially negative, because the monoaminergic systems have driven an adaptation, so when we return to the initial situation we may find ourselves a bit lost. That’s a what we need to make people understand. Monoaminergic systems are also involved in how individuals evolve with age. Finally, these systems are also studied in neuropharmacology to treat depression, anxiety, schizophrenia, and so on. The study of monoamines can make an important contribution to society in this regard.

JGR: What have been the successes of the pharmaceutical industry?

PDD: Many pharmacological treatments have arisen by chance. Random is wise. What the industry does is to try to explain the mechanisms of action by observing how the molecules work in the nervous tissue. This is the case with schizophrenia, depression, anxiety, and so on. We still do not understand neurodegenerative diseases. We are making progress, a considerable effort is being made, but we do not understand them very well. We don’t understand epilepsy either, by the way. The success of the pharmaceutical industry is based on the discoveries of researchers, which is what allows the development of more effective molecules. The obvious success of most of these pharmacological agents, be it L-DOPA, antidepressants or antipsychotics, is to limit side effects and improve pharmacokinetics (better and wider distribution in the body). Significant progress has been made in this area. But we need new advances because we are running out of steam.

In the case of Alzheimer’s, antibodies are starting to be developed. But I don’t know if we have the necessary handsight to evaluate their success. We will have to wait about 5-10 years to see if all this is functional. The Parkinson’s case was different. We had an incredible stroke of luck. Before L-DOPA we knew that atropine could correct Parkinson’s, albeit with significant side effects. But for the moment we cannot correct Alzheimer’s disease. We don’t understand it. Probably what we need is to address its causes.

JGR: What do you think about basic research (as opposed to applied research)? Is it legitimate to study protein X as an end, or should it be implicated in the aetiology of cancer?

PDD: Applied research is what we call innovation. Unfortunately in France we have a ministry called the Ministry of Research and Innovation, and that says a lot about the mentality of our government. But it is not the only thing. Our research has a scope of about 3 centimeters forth instead of looking ahead to the next 20 or 50 years, which is what basic or fundamental research does. People don’t understand what fundamental research is, because the more we individualize, the more we look at the short term. I think the need for society is to look very far ahead to reposition humanity and biology in general into a global understanding. I’ll tell you an example. I have done a lot of work with L-DOPA. Since 1960, L-DOPA has been administered because it is thought to increase dopamine in the striatum. Well, that may not be the case. Millions and millions of euros may have been spent to understand the impact of L-DOPA on striatal dopamine and striatal mechanisms. It may not work that way, maybe everything is bogus. That is innovation. You can develop something within a defined theoretical framework. The problem is that this theoretical framework may be wrong. Fundamental research is all about this. It systematically studies the theoretical framework.

JGR: Recently, members of the European Parliament have spoken out against animal experimentation and have called for a transition to non-animal research. What is your opinion on this?

PDD: I think this issue is beyond the scientific opinion. It is both passionate and political. If we talk about the scientific aspect, I go back to the beginning of the interview: how do we study how the brain works? And there you have my answer. With behavior. A brain outside the skull has no function. You can study the gut in a Petri dish: you add histamine and it contracts. You can study the heart outside the body: add noradrenaline and it pumps. You can study muscle, adding noradrenaline or acetylcholine and seeing what happens. But if you take a brain out of the skull, you have no idea of what’s going on. An animal reacts according to its environment, and I’m not just talking about humans. Take the example of dolphins stranded on the shore. What’s going on here? We’re not going to find an answer by just looking at one of its cells. The debate is not scientific, and I think the politicians are not explaining it well. They should explain that you can’t find an Alzheimer’s drug by looking at cells. Still, we can consider the complete opposite opinion: a total rejection of life alteration. Why not? But then we can’t ask for wonderful research. It is curious because when we talk about animal research we are talking about all animals. Even the snail. But at the moment there is no problem if we crush a snail.

JGR: How do you see the future of the Academy in the short term?

PDD: There are disparities in Europe in terms of how it works. For example, take the Latin countries: Spain, Italy, France. These countries had a rather republican system, with lifetime positions. This system is beginning to disappear in France, and probably also in Spain and Italy. Research and researchers are beginning to turn to Europe, which offers large calls for projects. This was already very popular in Germany, the United Kingdom, Sweden, the Netherlands, etc. Gradually, these countries (Spain, France and Italy) are beginning to rethink their organization in terms of civil servants. The request from Europe for some countries, including France, is to reduce their expenses in general, and this includes the number of civil servants. So I see the future of the Academy drifting towards an Anglo-Saxon system. The government that was funding the universities will eventually disappear, the universities will become autonomous. This is how it is going to be. In a few years, the price of tuition will skyrocket. This is something I regret, but I see Europe as a steamroller. If you don’t fit into the system, it means you’re on the margins, with greater difficulty to get a contract. Meanwhile universities are specializing and developing sectors with people that review projects and make them a bit sexier. The system is drifting into something I don’t like.

JGR: What have you learned during your years of research?

PDD: I have learned that at the beginning you don’t know your question. Your question arises from multiple sources, from many readings. In basic research, the researcher has to find what he is looking for. This has nothing to do with innovation. In general, it is a question that is a bit impalpable. If we go back to the beginning of the interview: how do we approach the study of a certain topic? How do we position ourselves? There are different scales. There are those who take the cell perspective, others the in vitro systems, others rather the in vivo systems and the integration, and others absolutely need to study behavior.

JGR: Do you remember any good advice you were given?

PDD: Yes. It was after my postdoc, and it was given to me by the director of the lab where I did it, who was also a neurochemist. I started to feel neurochemistry was somehow disappearing. It seemed to me that the neurochemistry I was using then was getting a little bit outdated. But my director told me: don’t give it up, it will come back. I learned that there were cycles. I don’t like cycles. But this means that we are driven by trends and fashions. For example, there are labs that are diving into optogenetics without really knowing what that entails.

JGR: Do you have a book to recommend?

PDD: Awakenings, by Oliver Sacks.

JGR: Do you have a message for readers?

PDD: Neuroscience research continues, for better or worse. I think basic research is still the driving force. Applied research should not be the model, because too much money is spent and it is very time-limited. Basic research is more difficult to tackle, but it has a greater impact.

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