Summary: In mice, exposure to THC caused sustained activation of mitochondrial cannabinoid receptors in astrocytes, triggering a molecular cascade that disrupted glucose metabolism. Astrocytes’ capacity to convert glucose into lactate—the metabolic “fuel” neurons rely on—was reduced, impairing neuronal function and diminishing social behavior for up to 24 hours after cannabis exposure.
Source: INSERM
Regular cannabis exposure can negatively affect sociability. Some users experience withdrawal and diminished social interactions, but the brain circuits and cellular mechanisms behind these effects have been unclear—until now.
To clarify those mechanisms, a team led by Inserm researcher Giovanni Marsicano at NeuroCenter Magendie (Inserm/Université de Bordeaux) collaborated with researchers from the University of Salamanca led by Juan Bolaños. Their joint effort focused on how cannabinoid receptors—brain proteins that interact with cannabis compounds—affect brain metabolism and behavior.
The study, published in the journal Nature, identifies a chain of events linking cannabis exposure to altered social behavior. The researchers found that activating specific cannabinoid receptors located on mitochondria within astrocytes—the star-shaped glial cells that regulate brain energy supply—leads to metabolic dysfunction that harms neuronal activity and social interactions.
Cannabinoid receptors on mitochondria in astrocytes
This research builds on earlier work from 2012 when Marsicano’s lab discovered cannabinoid receptors exist not only on cell membranes but also on mitochondrial membranes. In the new study, the team focused on those mitochondrial cannabinoid receptors (referred to as mtCB1) within astrocytes. Astrocytes are essential for brain energy metabolism: they take up glucose from the blood, metabolize it to lactate, and supply that lactate to neurons as fuel. Because astrocyte metabolism directly supports neuronal activity and behavior, the team investigated how mtCB1 activation affects these processes.
When mice were exposed to THC, the primary psychoactive component of cannabis, persistent activation of astrocyte mtCB1 receptors initiated a cascade of molecular changes that impaired astrocytic glucose metabolism. As astrocytes’ ability to produce lactate declined, neurons received less metabolic support. The resulting energetic shortfall compromised neuronal function and produced measurable behavioral effects: social interaction was notably reduced for as long as 24 hours after THC exposure.
According to Marsicano, the study provides the first clear demonstration that sociability declines sometimes linked to cannabis use can be traced to altered glucose metabolism in the brain. The findings highlight astrocyte energy metabolism as a direct regulator of behavior and open new paths for research into therapeutic strategies that could prevent or reverse the behavioral effects of cannabis exposure.
The authors also note the broader clinical relevance: as discussions about therapeutic cannabis grow, it is important to map which cannabinoid receptors mediate beneficial versus harmful effects. Understanding how different receptors—especially mitochondrial receptors in astrocytes—respond to cannabinoids will help refine treatment approaches and better manage patients who may receive cannabis-based therapies.
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Original Research: Open access
“Glucose metabolism links astroglial mitochondria to cannabinoid effects” by Daniel Jimenez-Blasco, Arnau Busquets-Garcia, Etienne Hebert-Chatelain, Roman Serrat, Carlos Vicente-Gutierrez, Christina Ioannidou, Paula Gómez-Sotres, Irene Lopez-Fabuel, Monica Resch-Beusher, Eva Resel, Dorian Arnouil, Dave Saraswat, Marjorie Varilh, Astrid Cannich, Francisca Julio-Kalajzic, Itziar Bonilla-Del Río, Angeles Almeida, Nagore Puente, Svein Achicallende, Maria-Luz Lopez-Rodriguez, Charlotte Jollé, Nicole Déglon, Luc Pellerin, Charlène Josephine, Gilles Bonvento, Aude Panatier, Beat Lutz, Pier-Vincenzo Piazza, Manuel Guzmán, Luigi Bellocchio, Anne-Karine Bouzier-Sore, Pedro Grandes, Juan P. Bolaños & Giovanni Marsicano. Nature
Abstract
Glucose metabolism links astroglial mitochondria to cannabinoid effects
Astrocytes absorb glucose from the bloodstream and convert it into energy substrates that sustain neuronal activity and behavioral responses. They are also regulated by neuronal signaling through membrane receptors. Whether activation of astroglial receptors can directly modify cellular glucose metabolism and thereby influence behavior has been uncertain. This study demonstrates that activating mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB1) disrupts glucose metabolism and reduces lactate production in the brain, producing altered neuronal function and impaired social behaviors. Mechanistically, mtCB1 activation lowers phosphorylation of the mitochondrial complex I subunit NDUFS4, reducing complex I stability and activity. That change decreases astrocytic generation of reactive oxygen species and interferes with glycolytic lactate production via the hypoxia-inducible factor 1 pathway. The metabolic consequences create neuronal redox stress and measurable deficits in social interaction. Genetic or pharmacological interventions that correct each step in this pathway prevent the behavioral effects of cannabinoid treatment. These findings indicate that mtCB1 receptor signaling can directly regulate astroglial glucose metabolism to modulate neuronal activity and social behavior in mice.