The medial prefrontal cortex (mPFC) is involved in cognitive and emotional functions housing neurons and astrocytes, impacting mPFC activity. To this end, astrocytes express several GPCR to fine-tune synaptic transmission such as CB1R and adenosine A1 and A2A receptors (A1R, A2AR). Since interactions of these receptors in astrocytes are not known, this work aims to fill the gap of the crosstalk between CB1R and adenosine receptors and their contribution for mPFC synaptic plasticity.CB1R-A1R and CB1R-A2AR complexes were observed in primary cultures of astrocytes, by using Proximation Ligation assay and BRET assay. Additionally, in primary cultures of astrocytes incubated with FURA-2AM, it was observed that CB1R-mediated Ca2+ transients were increased and decreased when A1R and A2AR were activated, respectively, unveiling adenosine receptors as modulators of astrocytic CB1R. Field-excitatory post-synaptic potentials were recorded in mPFC from IP3R2WT and IP3R2KO slices and the magnitude of long-term potentiation (LTP) was evaluated. In IP3R2WT, CB1R activation significantly increased LTP magnitude, an effect that is under the control of A1R but not A2AR. Notably, in IP3R2KO mice, that lack bulk astrocytic Ca2+ elevations, CB1R activation decreases LTP, and this effect is not changed by A1R or A2AR. Moreover, IP3R2KO mice exhibit a higher LTP magnitude compared to IP3R2WT probably due to a decrease in the GABAergic signaling.The present work suggests that CB1R have a homeostatic role on mPFC LTP, under the control of A1R, probably due to physical crosstalk between these receptors in astrocytes that ultimately alters CB1R Ca2+ signaling.