Scientists have just identified in the mouse, and then confirmed in humans, a new factor that regulates addiction. Glutamate, a neurotransmitter[1], contributes to regulating dopamine release in the nucleus accumbens, one of the cerebral structures of the reward system. More precisely, it is its subtle balance with another neurotransmitter – acetylcholine – that prevents up-regulation of the system and entry into addiction. This discovery, which opens up new therapeutic perspectives, was made by neurobiologists in the Neurosciences Paris-Seine laboratory (Institut de Biologie Paris-Seine, CNRS/Inserm/UPMC) and the Douglas Mental Health University Institute (McGill University, Montreal, Canada), working in association with human genetics specialists at Institut Mondor de Recherche Biomédicale (Inserm/UPEC). Their work was published on 4 August 2015 in Molecular Psychiatry.

In the context of drug taking, dopamine levels rise in the cerebral structures that form the reward system.  The intensity and rapidity of dopamine release provide a basis for the processes that will lead to the development of addiction. The cholinergic neurons in the nucleus accumbens, one of the centers of reward, are known to regulate this dopamine release. While most neurons only release a single neurotransmitter, a French-Canadian team led by CNRS researcher Salah El Mestikawy showed in 2002 that these acetylcholine-using neurons are also able to utilize glutamate. These neurons, which are to some extent “bilingual”, can thus both activate (via acetylcholine) and inhibit (via glutamate) dopamine secretion.

In this new study, much of it carried out by Diana Yae Sakae for her thesis project supervised by Salah El Mestikawy, the scientists showed that when they inhibited a gene essential to this signaling by glutamate (called VGLUT3) in mice, the animals became more vulnerable to cocaine. They experienced enhanced stimulant effects of the drug, developing “addiction” more easily and being more likely to “relapse” after a period of abstinence. The glutamate from these acetylcholine neurons therefore plays an important regulatory role in limiting cocaine addiction.

The scientists then wanted to determine whether this mechanism also applied to humans. In cocaine and/or opiate-dependent adults, they looked for mutations of the gene that had rendered the mice “addicted”. At the Institut Mondor de Recherche Biomédicale, Stéphane Jamain’s team observed that a mutation of this gene was ten times more common among severely dependent patients than in individuals without psychiatric symptoms. This mutation may explain the greater vulnerability to addiction of these patients[2]. In any case, these observations appear to confirm the role of glutamate in the addictive mechanism.

This work has thus clarified the neuronal mechanisms that underlie the search for hedonic sensations: contrary to what scientists thought until now, these findings show that it is not acetylcholine alone that regulates dopamine release, but a balance between acetylcholine and glutamate.

[1] In order to communicate, neurons use chemical substances called neurotransmitters. Conventional neurotransmitters include dopamine, serotonin, acetylcholine and glutamate, etc.

[2] That said, even within the group of severely dependent patients this mutation was only present in 5% of cases, indicative of the multifactorial nature of addiction and more generally the complexity of psychiatric diseases

Researchers from the Cognitive Neuroimaging Unit at NeuroSpin have just identified a network of areas of the brain that are organised in a way that could at least partially explain the specificity of the cognitive functions in the human species. These regions are specifically activated in humans, but not in the macaque monkey, in response to specific variations in the auditory sequences played. They coincide with the classic language areas, particularly Broca’s area. The human faculty of language could therefore have its origins in the emergence of a brain circuit capable of combining, in a single region, information coming from the other regions of the brain into a coherent whole. These results, obtained through a collaboration between the French Atomic Energy Commission (CEA), Inserm, Collège de France, Versailles-Saint-Quentin-en-Yvelines University and Paris-Sud University, are published in Current Biology.

In this study, conducted at NeuroSpin, Stanislas Dehaene (a professor at Collège de France, and director of the Inserm/CEA/Paris-Sud University Cognitive Neuroimaging Unit) and Bechir Jarraya (Professor of Neurosurgery at Versailles-Saint-Quentin-en-Yvelines University), together with Liping Wang and Lynn Uhrigh, used a noninvasive functional imaging method, 3 Tesla functional MRI. They exposed three macaque monkeys and twenty volunteers to regular auditory sequences, e.g. three identical sounds followed by a fourth different sound (a sequence notated as AAAB). Occasionally, they presented a sequence that violated this regularity, either because it included a different number of sounds (e.g. AAAAAB), or because the sequence of sounds was abnormal (e.g. AAAA, which does not end in a B sound).

The monkey’s brain reacted to changes in numbers and sequences, which denotes a certain capacity for abstraction. However, it did so in distinct areas, specialised for either number or sequence. In contrast, the human brain combined the two parameters in regions that coincide with the language areas.

Thus, whereas the monkeys detected isolated properties, such as “four sounds” or “the last one is different,” evolution seems to have endowed our species with a specific ability to combine these pieces of information into a coherent whole, a formula such as “three sounds, then another”—the very beginnings of an inner language?

This figure illustrates the unique ability of the human brain to combine pieces of abstract auditory information. Some regions of the brain are associated with the detection of a change in number of sounds by the brain, independently of a concomitant change in the sequence of sounds (red areas in the figure). Conversely, some regions of the brain detect changes in the sequence of sounds, independently of their number (green areas). In the monkey brain, these two sets of regions are unconnected. Places where they intersect (shown in yellow), i.e. regions that combine the two types of information, “change in sequence of sounds” and “change in number of sounds,” are found only in the human brain. All activations detected are projected on a lateral view of the right hemisphere for purposes of representation. © Liping Wang

Imagine being plunged into a world in which events did not always have the same consequences, and with rules that changed without your knowledge. How would you adapt? Uncertainty as a factor in decision making is a fundamental issue in general psychology. Our world turns out to be more or less predictable, and our brain has to adapt to this uncertainty to make the best possible choices in any situation. This is the subject that attracted Fabien Vinckier and Raphaël Gaillard, researchers at St Anne’s Hospital, Inserm and Paris Descartes University, in collaboration with Mathias Pessiglione, an Inserm researcher at the Brain and Spinal Cord Institute at Pitié–Salpêtrière Hospital, AP-HP, and Paul Fletcher, from the University of Cambridge in Great Britain. This study, which has been published in Molecular Psychiatry, reveals that our ability to adapt our decisions to the uncertainty inherent in any choice may be disrupted in the early stages of psychosis.

Participants were invited to play a computer game during which they had to decide whether to bet on symbols. The rules were not always applied, and were reversed from time to time (a symbol that always won money started to lose it, and vice versa). When subjected to these conditions, participants, in order to adapt their choices, had to be able to simultaneously detect changes in the rules of play and times of stability. It was possible to show, with the help of mathematical models, that to be most effective, participants use their confidence in the rules of play to make their choices.

In order to reproduce the conditions for the early stages of psychosis, participants were intravenously administered either a placebo or a very low dose of ketamine. Ketamine is an anaesthetic that is used daily in high doses in operating theatres, and which, at low doses, causes symptoms strongly resembling the early stages of a psychotic episode. Continuous measurement of the participants’ behaviour and brain activity using functional magnetic resonance imaging (fMRI) made it possible to identify the effects of ketamine.

Using this model, the researchers demonstrated that ketamine affects the ability of participants to distinguish times when the rules of play are stable, and optimise their behaviour accordingly.

Thus, they did not did not come to a point where they systematically bet on the winning symbol (i.e. betting 100% of the time, even though the symbol only actually won 80% of the time), as if a persistent doubt unsettled them. This impairment is correlated with a disturbance in the fronto-parietal brain network.

“This study characterises the key role of adaptation to uncertainty in decision-making, and its disruption in the early stages of psychosis. It should enable a better understanding of the onset of psychotic illness, and guide therapeutic innovation,” explains Raphaël Gaillard, Professor of Psychiatry at Paris Descartes University, and Head of the Department of Mental Health and Therapeutics at St Anne’s Hospital.

This study reveals, in a pharmacological model of psychosis, the disruption of a person’s ability to finely adapt his/her behaviour to the uncertain nature of the environment. The brain bases for this impairment have been identified (a fronto-parietal network), and can be linked to the molecular pathway on which ketamine acts, and which is currently the focus of a search for new treatments for schizophrenia.

These findings are a continuation of a publication that appeared in the journal Science (Whitson, Science, 2008) on the onset of apparently psychotic phenomena (superstitions, conspiracy theories) in people who are subjected to strong uncertainty. Some psychotic symptoms, such as the emergence of delusions, could be a type of inappropriate response to the inability to construct and maintain a stable representation of the world

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