The Two Endocannabinoids Talk to Different Brain Cells

What the researchers found

In the hippocampus, 2-AG activates CB1 receptors on neurons to depress synaptic transmission, while anandamide activates CB1 receptors on astrocytes to potentiate adjacent synapses. Only anandamide and astrocyte signaling were required for spike-timing-dependent long-term potentiation.

Why it matters

This discovery rewrites the textbook on endocannabinoid signaling. Instead of two redundant molecules doing the same job, 2-AG and anandamide have entirely separate cellular targets and produce opposing effects on brain communication.

The numbers in context

2-AG selectively depressed synaptic transmission via neuronal CB1 receptors. Anandamide selectively potentiated synapses via astrocyte CB1 receptors. Only anandamide was required for spike-timing-dependent long-term potentiation in the hippocampus.

How the study worked

Researchers used mouse hippocampal brain slices with pharmacological tools, genetic models, and electrophysiology to dissect which endocannabinoid signals to which cell type.

What this study cannot tell us

This was conducted in mouse hippocampal tissue, and it remains unclear whether the same cell-type specificity holds across all brain regions or in humans.

How to read the evidence

Published in Nature Neuroscience with robust pharmacological and genetic evidence across multiple experimental approaches.

When this study was published

2026 study representing cutting-edge neuroscience research.

The bigger picture

Understanding that each endocannabinoid has a distinct cellular target could reshape how researchers approach cannabis pharmacology. THC activates CB1 receptors on both neurons and astrocytes simultaneously, which may explain some of its complex and sometimes contradictory effects.

Questions still open

• Does THC disrupt this precise division of labor between 2-AG and anandamide? Could selectively targeting one endocannabinoid pathway offer therapeutic benefits without the side effects of broadly activating CB1 receptors?

Common questions

Read the original research

Distinct endocannabinoids specifically signal to astrocytes or neurons in the adult mouse hippocampus.

Nature neuroscience, 29(2), 445-454

Citation

Noriega-Prieto, Jose Antonio; Falcón-Moya, Rafael; Noeker, Jacob A; Cai, Ruyi; Fundazuri, Unai B; Eraso-Pichot, Abel; Cai, Shangxuan; Guttipatti, Pavan; Belisle, Lindsey; Rodríguez-Moreno, Antonio; van der Stelt, Mario; Li, Yulong; Cheer, Joseph F; Marsicano, Giovanni; Kofuji, Paulo; Araque, Alfonso. (2026). Distinct endocannabinoids specifically signal to astrocytes or neurons in the adult mouse hippocampus.. Nature neuroscience, 29(2), 445-454. https://doi.org/10.1038/s41593-025-02148-1

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