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Forty years of discoveries and surprises



An interview with Michel Hamon

Michel Hamon is honorary professor of neuropharmacology at the University Pierre and Marie Curie, Paris, and honorary director of research at the French Institut national de la santé et de la recherche médicale (INSERM). In recognition of his decades of ground-breaking research on the characterisation of serotonin and its receptors, he is this year’s recipient of the ECNP Neuropsychopharmacology Award. Ahead of the congress, he spoke about how his career unfolded, what research he is excited about today, and the importance of the supporting structures of peer review and communication.

Professor Hamon took up biochemistry at the prestigious École Normale Supérieure, where a friend introduced him to the prospect of working with Jacques Glowinski, who was returning from the US after working there with Julius Axelrod (who himself, along with Bernard Katz and Ulf von Euler, won the Nobel Prize in Physiology of Medicine in 1970). “Jacques Glowinski’s idea was to develop neuropharmacology in France,” explained Professor Hamon to ECNP. “He worked with dopamine, but the idea was to develop techniques to study other neurotransmitters, including serotonin, norepinephrine, acetylcholine, and so on.

“I had the opportunity to meet him at the end of 1967. I moved to his lab for the preparation of my master’s degree. Then I prepared my thesis on the biochemistry of serotonin, and the regulation of serotonin synthesis with the role of Trp hydroxylase (the key enzyme) and also the uptake of tryptophan in neurons.”
Professor Hamon then moved on to the regulation of serotonin synthesis: “This is really the beginning of my work in neuropharmacology,” he noted, “looking at the effect of drugs like selective serotonin reuptake inhibitors (SSRIs) or other antidepressants on the regulation of serotonin synthesis. I had the opportunity to publish a few papers at this time – papers which, for me, are really the reason I went on with serotonin research for over 40 years.”

In developing an understanding of the mechanisms and regulation of serotonin synthesis, it became clear that serotonin receptors played a key role in this regulatory process. SSRIs increase the extracellular concentration of serotonin, which acts upon serotonin receptors, which in turn, by feedback mechanisms, control the release and synthesis of serotonin.

“My first studies were looking at the results of administration of 5-HT agonists or antagonists on serotonin synthesis. This allowed us to infer that ligand-induced modifications in the serotonin synthesis rate due to the activation or blockade of receptors. From this, it was possible to characterise the agonist or antagonist properties of new ligands at the level of the receptors.”

In the seventies, radioligand binding assays were developed, laying the foundation for the characterisation of receptors in qualitative and quantitative terms. “This marked the beginning of the 5-HT1A receptor story in the INSERM research unit I had the fortune to set up in 1985 with excellent colleagues and friends,” said Professor Hamon, who developed the first selective 5-HT1A receptor radioligand.

“This research in my lab went on for about 20 years: determinations of the regional, cellular and subcellular distributions of the receptor thanks to the development of specific antibodies, identification of the receptor complex, and the various proteins that are coupled to the receptor itself, which explain all the downstream signalling mechanisms triggered by its activation. In parallel, functional studies allowed the demonstration of the differential roles of 5-HT1A autoreceptors on serotonergic neurons in the Raphe area versus postsynaptic 5-HT1A receptors in various central areas in the control of anxiety- and depression-related behaviours, impulsivity, sleep mechanisms and pain, using various animal models.

“The same strategy was subsequently applied to the study of other receptor types – the 5-HT1B and the 5-HT3 – for which we developed specific antibodies (against the 5-HT3A and 5-HT3B subunits) and characterised their respective cartographies in the rat brain and spinal cord, and the subcellular distribution of these receptors, including in peripheral tissues (blood vessels, intestine). We also made anti-5-HT6 receptor antibodies; we were the only lab to successfully develop these, and these allowed the further characterisation of this receptor type, notably on the primary cilia of neurons in the rat brain.”

“For the 24-year life history of my INSERM research unit at the faculty of medicine at Pitié-Salpêtrière in Paris, we focused mainly on basic neuroscience using validated animal models, but we always kept in mind its translational value for human health and diseases. Indeed, we also had opportunities to collaborate with several psychiatry departments notably for the identification of polymorphisms of genes encoding various serotonin receptors or the serotonin transporter (5-HTT) possibly associated with schizophrenia (5-HT2A), eating disorders (5-HT6), alcohol dependence (5-HT1B), and suicide (5-HTT).

In recent years, Michel Hamon has focused mainly on the pain field, for which serotonin is a key modulator through the implications of almost all 5-HT receptor types. “This was also the opportunity to discover some very strange mechanisms that seem paradoxical although it’s not the case – where you can have the same effects with an agonist and an antagonist of a given receptor type, namely the 5-HT7 receptor. This can be explained by the different brain circuits – activated by a 5-HT7 agonist acting on all receptors, including those which may not be normally activated by endogenous serotonin – or disinhibited by a 5-HT7 antagonist via the blockade of only those receptors which are activated by endogenous serotonin.”

Indeed, this formed one aspect of his Neuropsychopharmacology Award lecture at the recent 30th ECNP Congress in Paris. “My focus is on a few matters regarding the serotonin receptors,” explained Professor Hamon. “I also show why, from the simulation of a single receptor types, you can obtain various effects. “I describe further what is going on in the downstream pathways, and focus a little bit on the 5-HT effects which are independent of receptors – like the serotonylation process of small GTPases. This is probably the mechanism that explains the development of pulmonary arterial hypertension (PAH), with the 5-HT-dependent proliferation of muscle cells in the walls of pulmonary arteries. In this field, we contributed to showing that 5-HT internalisation through the 5-HT transporter expressed by muscle cells is required for PAH development and that 5-HT transporter inhibitors, the SSRIs, protect from this disorder in validated rat and mouse models. I also talk a little bit about what can happen with such drugs at various times of life – why, when you modulate serotonin receptor activity at given periods very early during life, you can produce effects which are in fact opposite to what is observed with the same drug during adult life…we have to be very careful using drugs acting on serotonin during brain growth.”

Serotonin plays a key role in the regulation of cytokines, he explained, with pain (a research area he is presently heavily involved with) being mediated by the release of proinflammatory cytokines. Connecting the dots across the psychiatric sphere, he continued: “We know now that in a relatively large proportion of depressed people there are increased basal levels of proinflammatory cytokines in blood. This is most often associated with the severity of depression and associated pain. “The idea is to go deeper into this field, to understand exactly what is going on with the interactions between the neurons and inflammatory cells. What is the exact role of the inflammatory reactions in depression and other psychiatric diseases? In particular, in schizophrenia, you also have evidence of peripheral inflammation which is correlated with increased inflammation in the brain and activation of microglia.”

Professor Hamon has been highly active over the years in science communication. He acted for many years as deputy chief editor of the Journal of Neurochemistry, executive editor of Naunyn-Schmiedeberg’s Archives of Pharmacology and Neurochemistry International, and field editor of the World Journal of Biological Psychiatry and of Clinical Neuropharmacology. Presently, he is still a member of the Editorial Boards of the latter two journals and L’Encéphale, European Journal of Pharmacology, and Fundamental and Clinical Pharmacology.
“For me, it was very important to play a role in the management of research at the national level and to identify the best people in my own field and to promote them – to put forward the topics on which they are working.

“This is why I have been involved first in the French Society for Neuroscience – I was its president from 1999 to 2001. I was also the president of the French Association for Biological Psychiatry and Neuropsychopharmacology ten years later. I was very much involved in ECNP as treasurer. Most importantly for me is the role as chairman of the Scientific Programme Committee for three successive ECNP congresses (2010-2012). In fact, altogether, I have been involved in the programme of ECNP Congress for about ten years. My objective was really to promote the activities of people for whom I was fully convinced of their contribution to basic and applied neurosciences.”

Professor Hamon is currently involved with the Union Nationale de Familles et Amis de Personnes Malades et/our Handicapées Psychiques (UNAFAM), an association which represents and advocates for families and friends of those affected by psychiatric illness. Founded in 1963, it has around 14,000 members, and is the largest association of its kind in France. UNAFAM strongly supports brain research, and Professor Hamon is president of the association’s scientific committee.

Michel Hamon has delivered his ECNP Neuropsychopharmacology Award lecture, ‘A journey into serotonin: 40 years of discoveries and surprises’ (PL.04) during the 30th ECNP Congress in Paris, on Monday 4 September.

You can view the webcast of his lecture. It's free of charge, only requires registration/login to the webpage.

Another highlight is the special interview, filmed at the 30th ECNP Congress.

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