Novel Neuroactive Molecules – The main focus of our research aims at furthering our understanding of the diversity of brain function by identifying and studying novel molecules which mediate synaptic transmission. Synaptic transmission is the mechanism which underlies the biochemical reactions that make brain functions and relies on the recognition of neurotransmitters and neuropeptides by their specific receptors. From genomic analyses we evaluate that we now know only a portion of all the transmitters that direct brain function. Our aim is to isolate novel neurotransmitters or neuropeptides and to study their physiological implications.
Among the receptors that direct brain functions, the most numerous are the G protein-coupled receptors (GPCRs). Among all the GPCRs that have been cloned some do not bind any of the presently known neurotransmitters or neuropeptides, these are the “orphan” GPCRs. We believe that these orphan receptors recognize thus far undescribed transmitters. This led us to use orphan GPCRs as targets for the identification and isolation of their specific natural ligands, that they purify from brain extracts. The natural ligands are then characterized biochemically, pharmacologically and physiologically to demonstrate that they are novel neurotransmitters or neuropeptides. We were the first in 1995 to ever isolate a novel ligand through this approach and isolated and characterized the neuropeptide orphanin FQ or nociceptin. Since then, this approach has been used around the world to identify the receptors of a dozen of new neuropeptides.
The second phase of our studies consists in determining the biological significance of the novel neurotransmitters or neuropeptides. Toward this goal, we define the novel neurotransmitters and neuropeptides tissue distribution and neuronal pathways. We then determine, by administering the novel neurotransmitters or neuropeptides to animals, whether they affect behavior and which particular responses are modulated. We have showed for example that orphanin FQ attenuates behavioral responses to stress. We have also shown that another neuropetide found via the orphan receptor strategy, prolactin-releasing peptide, suppresses absence seizures and promotes awakening by modulating the AMPA neurotransmission. Because neurotransmitters and neuropeptides can have a broad spectrum of effects, this part of our approach is often open-ended and is therefore combined to two different approaches. The first one is to engineer strains of mice genetically devoid of the novel neurotransmitter or neuropeptide and to compare the genetically-altered mice in the absence or upon the addition of the novel neurotransmitter or neuropeptide. The second one is to screen for molecules (antagonists or agonists) that can be used in behavioral experiments in controlled conditions. For example, we have recently shown that a synthetic molecule is able to decrease food intake by blocking a recently-deorphanized GPCR system.
Together these studies lead us towards the ultimate goal of our research, to find out whether the novel neurotransmitter or neuropeptide systems can be of use in treating human disorders.