A team from the University of Lausanne has discovered the dual role of orexins–molecules involved in narcolepsy–which are suspected of playing a role in certain neuropsychiatric disorders, such as attention-deficit disorder with or without hyperactivity or addictions.
Neurones mésencéphaliques dopaminergiques (rouges) de souris dépourvues d’OX2R (remplacé par un marqueur vert) * Open Access © Creative Commons (M. Bandarabadi et al., 2023)
Neuropsychiatric disorders, such as depression, schizophrenia, or certain addictions, are often linked to a dysfunction of dopamine, a brain chemical involved in motivation, pleasure, learning, and social interactions. In the brain, a region called the ventral tegmental area (or VTA) plays a central role in these processes: it is here that a certain type of neuron–known as dopaminergic neurons because they communicate with one another via dopamine–exhibits impaired function in many neurological and psychiatric disorders.
Among the molecules that influence this system, orexins–small neuropeptides produced in the hypothalamus, another region of the brain–are known to regulate wakefulness, sleep, appetite, as well as stress and mood. The study of the interactions between orexins and dopaminergic neurons is at the heart of the research topics pursued by Dr. Anne Vassalli’s laboratory within the Department of Biomedical Sciences (DSB) of the Faculty of Biology and Medicine at the University of Lausanne. One of the main goals is to better understand the origins of certain psychiatric disorders.
International Interest in Orexins
This year, the Albert Lasker Award for Basic Medical Research recognized work demonstrating the role of orexins in narcolepsy, and it was also in 2026 that the first OX2R agonist, oveporexton, was approved by the United States and China for the treatment of this sleep disorder. Orexins are therefore currently in the spotlight, and Anne Vassalli’s research group has contributed to this field: in an article published in October in *Biological Psychiatry*, the Lausanne-based team highlights a new mechanism by which these neuropeptides modulate the dopaminergic system. These neuropeptides reveal their dual nature: on the one hand, orexin A activates dopaminergic neurons in the VTA region by acting on the OX1R receptor; on the other hand, orexin B inhibits them via the OX2R receptor.
To make this discovery, the scientists developed mice lacking one or the other of the orexin receptors–OX1R or OX2R–in their dopamine neurons. These models made it possible to study the role of these small molecules in a living organism, particularly their influence on neuronal electrical activity as well as on social and emotional behaviors. The stimulating effect of this peptide on neurons, which was already well documented, has been confirmed. It acts through the OX1R receptor, which is activated by type A orexin. “For the first time, we show that another type of orexin, orexin B, has a completely opposite effect, mediated by the OX2R receptor. “This was unexpected,” says Dr. Stamatina Tzanoulinou, the study’s first author.
A potential avenue for treating OCD, ADHD, and ASD?
Furthermore, the cognitive and socio-emotional abilities of the mice are affected differently depending on which receptor is knocked out. The loss of OX1R increases anxiety and hyperactivity, while the loss of OX2R reduces sociability and disrupts certain forms of learning, though it enhances others. However, the absence of either receptor leads to compulsive and impulsive behaviors in both cases. “These results could not have been obtained without the experiments on laboratory mice,” comments Anne Vassalli, the article’s last author.
This new brain mechanism could therefore serve as a therapeutic target for neuropsychiatric disorders characterized by altered states of arousal, such as obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). However, it is still too early to say for certain. The observations made in mice by biologists at the University of Lausanne, in collaboration with EPFL and the University of Milan-Bicocca, will still need to be clinically confirmed. In the case of narcolepsy, as patients are set to be treated with OX2R agonists, this study raises another crucial question: it will be necessary to determine whether prolonged stimulation of this receptor could lead to side effects on social interactions, emotional state, or learning in humans.
* Full image caption: Shown in red are the dopaminergic neurons in the mesencephalic region, including the ventral tegmental area (VTA), of the brains of mice lacking OX2R, the type 2 orexin receptor. Neurons that have specifically lost OX2R, which has been replaced by a green marker, are shown in green.