Amphetamine disrupted a form of endocannabinoid-dependent brain plasticity in the reward center of male but not female mice, and this sex difference was traced to CB1 receptors on astrocytes.
Neuroscience researchers and anyone interested in sex differences in drug responses and the role of the endocannabinoid system in addiction.
Sex-specific endocannabinoid mechanism in the reward center identified
What the researchers found
Amphetamine impaired astroglial CB1 receptor-dependent synaptic plasticity in the nucleus accumbens of male mice but not females. The locomotor effects of amphetamine required astroglial CB1 receptors in males but not females. This reveals a previously unknown sex-dependent mechanism through which the endocannabinoid system mediates stimulant drug effects.
Why it matters
Sex differences in addiction are well-documented but poorly understood. This study identifies a specific cellular mechanism - CB1 receptors on astrocytes in the reward center - that may help explain why stimulant drugs affect men and women differently, with broader implications for understanding sex differences in substance use disorders.
The numbers in context
Amphetamine impaired astroglial CB1-dependent plasticity in male NAc but not female. Locomotor effects required astroglial CB1 in males only. The astrocyte-specific manipulation (AstroLight tool) isolated the cell type responsible.
How the study worked
Researchers used mice with astrocyte-specific CB1 receptor deletions and standard CB1 mice. Synaptic plasticity was measured in nucleus accumbens slices. Behavioral effects of amphetamine (locomotor activity) were compared between males and females and between mice with and without astroglial CB1 receptors.
What this study cannot tell us
Mouse-specific findings may not directly translate to humans. The study focused on amphetamine, not cannabis directly. The specific astrocyte manipulation tools used are relatively new and the full implications of astrocyte-specific CB1 deletion are still being explored.
How to read the evidence
Elegant mechanistic animal study using cell-type-specific genetic tools. Strong basic science evidence but focused on amphetamine with indirect cannabinoid relevance.
When this study was published
Published in 2025.
The bigger picture
Astrocytes were long considered passive support cells, but this study shows they actively shape how drugs affect brain circuits. The finding that the same receptor on the same cell type has different functional importance in males versus females adds a new dimension to both cannabinoid and addiction research.
Questions still open
- Do astroglial CB1 receptors also mediate sex differences in cannabis effects? Could targeting astrocytic endocannabinoid signaling offer sex-specific addiction treatments?
Common questions
What are astrocytes?
How does this relate to cannabis?
Read the original research
Astroglial CB1 Reveal Sex-Specific Synaptic Effects of Amphetamine.
Glia, 73(8), 1673-1691
Citation
Mariani, Yamuna; Dalla-Tor, Tommaso; Garavaldi, Tommaso; Julio-Kalajzić, Francisca; Gisquet, Doriane; Gomez-Sotres, Paula; Cannich, Astrid; Gambino, Giuditta; Drago, Filippo; Serrat, Roman; Hurel, Imane; Chaouloff, Francis; Pouvreau, Sandrine; Bellocchio, Luigi; Marsicano, Giovanni; Covelo, Ana. (2025). Astroglial CB1 Reveal Sex-Specific Synaptic Effects of Amphetamine.. Glia, 73(8), 1673-1691. https://doi.org/10.1002/glia.70026
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