Localization and Mechanisms of Action of Cannabinoid Receptors at the Glutamatergic Synapses of the Mouse Nucleus Accumbens

Despite the role of excitatory transmission to the nucleus accum-bens (NAc) in the actions of most drugs of abuse, the presence and functions of cannabinoid receptors (CB1) on the glutamater-gic cortical afferents to the NAc have never been explored. Here, immunohistochemistry has been used to show the localization of CB1 receptors on axonal terminals making contacts with the NAc GABAergic neurons. Electrophysiological techniques in the NAc slice preparation revealed that cannabimimetics [WIN 55,212,2 (WIN-2) and CP55940] strongly inhibit stimulus-evoked gluta-mate-mediated transmission. The inhibitory actions of WIN-2 were dose-dependent (EC50 of 293 6 13 nM) and reversed by the selective CB1 antagonist SR 141716A. In agreement with a pre-synaptic localization of CB1 receptors, WIN-2 increased paired-pulse facilitation, decreased miniature EPSC (mEPSC) frequency, and had no effect on the mEPSCs amplitude. Perfusion with th