CB1 receptor activation inhibits neuronal and astrocytic intermediary metabolism in the rat hippocampus

Cannabinoid CB1 receptor (CB1R) activation decreases synaptic GABAergic and glutamatergic transmission and it also controls peripheral metabolism. Here we aimed at testing with 13C NMR isotopomer analysis whether CB1Rs could have a local metabolic role in brain areas having high CB1R density, such as the hippocampus. We labelled hippocampal slices with the tracers [2-13C]acetate, which is oxidized in glial cells, and [U–13C]glucose, which is metabolized both in glia and neurons, to evaluate metabolic compartmentation between glia and neurons. The synthetic CB1R agonist WIN55212-2 (1 μM) significantly decreased the metabolism of both [2-13C]acetate (−11.6 ± 2.0%) and [U–13C]glucose (−11.2 ± 3.4%) in the tricarboxylic acid cycle that contributes to the glutamate pool. WIN55212-2 also significantly decreased the metabolism of [U–13C]glucose (−11.7 ± 4.0%) but not that of [2-13C]acetate contributing to the pool of GABA. These effects of WIN55212-2 were prevented by the CB1R antagonist AM251 (500 nM). These results thus suggest that CB1Rs might be present also in hippocampal astrocytes besides their well-known neuronal localization. Indeed, confocal microscopy analysis revealed the presence of specific CB1R immunoreactivity in astrocytes and pericytes throughout the hippocampus.In conclusion, CB1Rs are able to control hippocampal intermediary metabolism in both neuronal and glial compartments, which suggests new alternative mechanisms by which CB1Rs control cell physiology and afford neuroprotection.

► Hippocampal CB1R activation decreases [2-13C]acetate metabolism into glutamate.
► CB1R activation also decreases [U–13C]glucose metabolism into glutamate and GABA.
► Hence, this control by CB1Rs of the TCA cycle occurs both in neurons and glia.
► We found specific CB1R immunoreactivity in hippocampal astrocytes.
► This control of the TCA cycle may affect synaptic plasticity and neuroprotection.