Exercise craving potentiates excitatory inputs to ventral tegmental area dopaminergic neurons
Maria‐Carmen Medrano, Imane Hurel, Emma Mesguich, Bastien Redon, Christopher Stevens, François Georges, Miriam Melis, Giovanni Marsicano, Francis Chaouloff
Addiction Biology. 2020-10-05; :


Physical exercise, which can be addictogenic on its own, is considered a therapeutic alternative for drug craving. Exercise might thus share with drugs the ability to strengthen excitatory synapses onto ventral tegmental area (VTA) dopaminergic neurones, as assessed by the ratio of AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) to NMDA receptor (NMDAR)-mediated EPSCs. As did acute cocaine, amphetamine, or Δ9 -tetrahydrocannabinol (THC) pretreatments, an acute 1-h wheel-running session increased the AMPAR/NMDAR ratio in VTA dopaminergic neurones. To dissect the respective influences of wheel-running seeking and performance, mice went through an operant protocol wherein wheel-running was conditioned by nose poking under fixed ratio schedules of reinforcement. Conditioned wheel-running increased the AMPAR/NMDAR ratio to a higher extent than free wheel-running, doing so although running performance was lower in the former paradigm than in the latter. Thus, the cue-reward association, rather than reward consumption, played a major role in this increase. The AMPAR/NMDAR ratio returned to baseline levels in mice that had extinguished the cued-running motivated task, but it increased after a cue-induced reinstatement session. The amplitude of this increase correlated with the intensity of exercise craving, as assessed by individual nose poke scores. Finally, cue-induced reinstatement of running seeking proved insensitive to acute cocaine or THC pretreatments. Our study reveals for the first time that the drive for exercise bears synaptic influences on VTA dopaminergic neurones which are reminiscent of drug actions. Whether these influences play a role in the therapeutic effects of exercise in human drug craving remains to be established.

Luigi Bellocchio (Marsicano team) and al. in eLife

Cannabis is the most common illicit drug of abuse in the US and globally. In addition, many states in the US, as well as several countries in the world, have legalized the medical and/or recreational use of cannabis. In this rapidly expanding landscape of cannabis use, huge efforts are made to find innovative interventions reducing potential cannabis-evoked harms. Here, we investigated the possible relation between cannabinoids and autophagy, the process of programmed cell “self-digestion”, and asked whether it could be related to the control of motor coordination behavior, one of the best established neurobiological processes impacted by cannabinoids.

We showed that Δ9-tetrahydrocannabinol, the major psychoactive ingredient of cannabis, impairs autophagy and accumulates P62 protein in neurons of the striatum, a brain area that plays a key role in the control of motor coordination. Second, we demonstrate that boosting autophagy, either by pharmacological manipulation (with the FDA-approved mammalian target of rapamycin inhibitor temsirolimus) or by dietary intervention (with the natural, non-toxic disaccharide trehalose), rescues the Δ9-tetrahydrocannabinol-induced impairment of striatal autophagy and motor coordination in mice. Furthermore, we provide evidence that cannabinoid CB1 receptors located on neurons of the striatal direct (stratonigral) pathway, by coupling to mammalian target of rapamycin activation and autophagy inhibition, are indispensable for the motor dyscoordinating activity of Δ9-tetrahydrocannabinol in mice.

Last but not least, using viral mediated genetic manipulation of striatonigral neurons we confirmed that disrupting mammalian target of rapamycin pathway, as well as boosting P62 accumulation in these cells, completely prevents Δ9-tetrahydrocannabinol-induced impairment of striatal autophagy and motor dyscoordination in mice.

Taken together, these findings identify impairment of autophagy as an unprecedented mechanistic link between cannabinoids and motor dyscoordination, and suggest that activators of autophagy might be considered as promising therapeutic tools to treat certain cannabinoid-evoked behavioral alterations.

Article

Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination. Cristina Blázquez, Andrea Ruiz-Calvo, Raquel Bajo-Grañeras, Jérôme M Baufreton, Eva Resel, Marjorie Varilh, Antonio C Pagano Zottola, Yamuna Mariani, Astrid Cannich, José A Rodríguez-Navarro, Giovanni Marsicano, Ismael Galve-Roperh, Luigi Bellocchio, Manuel Guzmán ; eLife 2020;9:e56811 doi: 10.7554/eLife.56811

https://elifesciences.org/articles/56811

Cannabis use can lead to effects in the brain that impact the normal functioning of users, including problems in sociability. The present paper - available now online and on July 23rd in press - explores how astrocytes, the most abundant brain cells, play a key role on the metabolic dysfunction associated with high doses of THC which results in decreased sociability in mice. The huge collaborative effort between the teams of Juan Bola–os in Salamanca and the Marsicano team allowed merging the expertise of the spanish team in brain bioenergetics and the expertise of our team in mouse in vivo experiments to better understand a novel way in which cannabinoids affect the brain.

In 2012, we showed that cannabinoid receptors are not only present on the cell membrane, but can also be present at mitochondria, the intracellular organelles whose role is to provide the cells with the energy they need [1]. This new study comes after showing that cannabinoid receptors are also located on the astroglial mitochondrial membranes [2]. These glial cells play a key role in brain energy metabolism as they transform glucose into lactate, which acts as "food" for neurons. Based on this, the paper explores how mitochondrial CB1 receptors impact astroglial bioenergetics both in vitro and in vivo. We first used astrocyte cultures where we observed that persistent activation of mitochondrial cannabinoid receptors destabilizes mitochondrial Complex I through the specific modulation of the phosphorylation status of NDUFS4, a C-I subunit important for its stability. A decrease of Complex stability decreases mitochondrial ROS levels in astrocytes affecting the activity of the transcription factor HIF1, a key regulator of glycolysis which leads to a dysfunction of glucose metabolism with a reduction of astroglial lactate levels. We next used a co-culture strategy to demonstrate that the astroglial bioenergetic alterations produced by the persistent activation of mitochondrial cannabinoid receptors resulted in an enhancement of mitochondrial ROS in neurons, among other bioenergetic alterations. In vivo, we used genetic approaches and NMR and FACS strategies to confirm the effects observed in cell cultures. We show that THC administration in mice reduces glucose-lactate conversion impacting the functioning of neurons by altering similar bioenergetic alterations. Interestingly, THC produces a persistent social interaction impairment still present 24 hours after administration that is not present in mice lacking astroglial CB1 receptors and is reversed by 1) manipulating the phosphorylation status of NDUFS4, 2) reducing neuronal mitochondrial ROS levels or 3) lactate supplementation. These findings not only suggest possible novel therapeutic targets to tackle negative effects of cannabis consumption or other conditions with social impairments, but highlight the fact that the interaction between different brain cells might be also very important to understand how the brain control our actions.

You can check the News and Views written about this study, which summarizes the main points of the paper in a very comprehensive way: https://www.nature.com/articles/d41586-020-01975-5

Contact Giovanni for any questions (Giovanni.marsicano@inserm.fr) and follow our twitter account for updates about publications and other science related events at @Marsicanolab




[1] Bénard, G., Massa, F., Puente, N., Lourenço, J., Bellocchio, L., Soria-Gómez, E., Matias, I., Delamarre, A., Metna-Laurent, M., Cannich, A., Hebert-Chatelain, E., Mulle, C., Ortega-Gutiérrez, S., Martín-Fontecha, M., Klugmann, M., Guggenhuber, S., Lutz, B., Gertsch, J., Chaouloff, F., López-Rodríguez, M. L., … Marsicano, G. (2012). Mitochondrial CB₁ receptors regulate neuronal energy metabolism. Nature neuroscience, 15(4), 558–564. DOI: 10.1038/nn.3053

[2] Gutiérrez-Rodríguez, A., Bonilla-Del Río, I., Puente, N., Gómez-Urquijo, S. M., Fontaine, C. J., Egaña-Huguet, J., Elezgarai, I., Ruehle, S., Lutz, B., Robin, L. M., Soria-Gómez, E., Bellocchio, L., Padwal, J. D., van der Stelt, M., Mendizabal-Zubiaga, J., Reguero, L., Ramos, A., Gerrikagoitia, I., Marsicano, G., & Grandes, P. (2018). Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus. Glia, 66(7), 1417–1431. DOI: 10.1002/glia.23314

Star-Shaped Brain Cells Shed Light on the Link Between Cannabis Use and Sociability

Press review:
- Communiqué de presse Inserm

- Bordeaux Neurocampus

- France 3 Nouvelle-Aquitaine

Cannabis use can lead to behavioral changes, including reduced social interactions in some individuals. To better understand the phenomenon, Inserm researcher Giovanni Marsicano and his team from NeuroCenter Magendie (Inserm/Université de Bordeaux), in collaboration with Juan Bolaños’ team from the University of Salamanca, have identified for the first time in mice the cerebral mechanisms underlying the relationship between cannabis and reduced sociability. Their findings have been published in Nature.

Regular exposure to cannabis may have a harmful impact on sociability. For some consumers, studies show that it may lead to withdrawal and reduced social interactions. However, the brain network and the mechanisms involved in this relationship were unclear until now.

In order to learn more about the subject, a group led by Inserm researcher Giovanni Marsicano at NeuroCenter Magendie (Inserm/Université de Bordeaux)[1] has joined forces with a Spanish team from the University of Salamanca led by Juan Bolaños[2].

More broadly, their work is aimed at improving our knowledge of how cannabinoid receptors (the brain receptors that interact with chemical compounds in cannabis) work.

In their study published in the journal Nature, the researchers show that after exposure to cannabis, behavioral changes related to sociability occur as a result of the activation of specific cannabinoid receptors, located in star-shaped cells of the central nervous system called astrocytes.

Cannabinoid receptors and mitochondria

These findings are the result of almost a decade of hard work. In 2012, Marsicano and his team had made a surprising discovery: cannabinoid receptors are not only present on the cell membrane, as previously believed. Some of these receptors are also located on the membrane of the mitochondria, the intracellular organelles whose role is to provide the cells with the energy they need.

This new study comes after the team has identified cannabinoid receptors located on the membrane of the mitochondria within astrocytes. Among other functions, these cells play a very important role in energy metabolism of the brain. They capture glucose from the blood and metabolize it into lactate, which acts as “food” for neurons. “Given the importance of astrocytes and energy use for brain function, we wanted to understand the role of these specific cannabinoid receptors and the consequences for the brain and behavior when exposed to cannabis,” explains Marsicano.

Researchers then exposed mice to the cannabinoid THC, the main psychoactive compound in cannabis. They observed that persistent activation of mitochondrial cannabinoid receptors located in astrocytes resulted in a cascade of molecular processes leading to dysfunction of glucose metabolism in astrocytes.

As a result, the ability of astrocytes to transform glucose into “food” for neurons was reduced. In the absence of the necessary energy intake, the functioning of neurons was compromised in the animals, with a harmful impact on behavior. In particular, social interactions were decreased for up to 24 hours after exposure to THC.

“Our study is the first to show that the decline in sociability sometimes associated with cannabis use is the result of altered glucose metabolism in the brain. It also opens up new avenues of research to find therapeutic solutions to alleviate some of the behavioral problems resulting from exposure to cannabis. In addition, it reveals the direct impact of astrocyte energy metabolism on behavior,” says Marsicano.

At a time when the debate over therapeutic cannabis is returning to the forefront, the researchers also believe that this type of work is needed to better understand how the body’s various cannabinoid receptors interact with the drug, and whether any of them are particularly associated with harmful effects. Such research would make it possible to ensure the optimal management of patients who might need this type of therapy.

[1] With Arnau Busquets-Garcia (now in Barcelona, Spain) and Etienne Hebert-Chatelain (now in Moncton, Canada)

[2] With Daniel Jimenez-Blasco

Ignacio Fernandez Moncada was born far away, in the colorful city of Valparaiso (Chili), that faces the Pacific Ocean. He is now a post-doc researcher at the Neurocentre Magendie, in Giovanni Marsicano’s team. Let’s meet him!