Previousfindings from our lab have demonstrated pharmacologically that the cannabinoidCB1 receptors (CB1Rs) within the nucleus accumbens core (NAcC) mediatesrestraint stress-induced reinstatement of extinguished cocaine-conditionedplace preference (CPP), through modulation of the context-specific glutamaterelease after stress. Given that restoration of impaired accumbal glutamatehomeostasis in cocaine-experienced rats prevented reinstatement, we proposedthat the underlying mechanism to explain our previous observations could berelated to the role of CB1R in modulating the basal extracellular glutamatelevels. For this purpose, we employed the reverse microdialysis technique tolocally and continuously perfuse increasing doses of ACEA, a highly selectiveCB1R agonist, and to collect extracellular glutamate within the NAcC of freelymoving rats. Results showed that ACEA caused a reduction in the basal levels ofextracellular glutamate in a dose-dependent manner. These in vivo findings areconsistent with the canonical mechanism of action described for CB1R inaccumbal slices and suggest that an initial reduction in basal levels ofextracellular glutamate might result in lower inhibition of mgluR2/3, favoringthe subsequent presynaptic glutamate release triggered by restraint stress inour model.