Endogenous cannabinoids (eCB) mediate synaptic plasticity in brain regions involved in learning and reward. Here we show that in mice, a single in-vivo exposure to Delta 9-tetrahydrocannabinol (THC) abolishes the retrograde signaling that underlies eCB-mediated synaptic plasticity in both nucleus accumbens (NAc) and hippocampus in vitro. This effect is reversible within 3 days and is associated with a transient modification in the functional properties of cannabinoid receptors.