TY - JOUR T1 - Localization and Mechanisms of Action of Cannabinoid Receptors at the Glutamatergic Synapses of the Mouse Nucleus Accumbens JF - The Journal of Neuroscience JO - J. Neurosci. SP - 109 LP - 116 DO - 10.1523/JNEUROSCI.21-01-00109.2001 VL - 21 IS - 1 AU - David Robbe AU - Gérard Alonso AU - Florence Duchamp AU - Joël Bockaert AU - Olivier J. Manzoni Y1 - 2001/01/01 UR - http://www.jneurosci.org/content/21/1/109.abstract N2 - Despite the role of excitatory transmission to the nucleus accumbens (NAc) in the actions of most drugs of abuse, the presence and functions of cannabinoid receptors (CB1) on the glutamatergic 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 glutamate-mediated transmission. The inhibitory actions of WIN-2 were dose-dependent (EC50 of 293 ± 13 nm) and reversed by the selective CB1 antagonist SR 141716A. In agreement with a presynaptic 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 the adenylate cyclase activator forskolin enhanced glutamatergic transmission but did not alter presynaptic CB1 actions, suggesting that cannabinoids inhibit glutamate release independently from the cAMP–PKA cascade. CB1 did not reduce evoked transmitter release by inhibiting presynaptic voltage-dependent Ca2+ currents through N-, L-, or P/Q-type Ca2+ channels, because CB1 inhibition persisted in the presence of ω-Conotoxin-GVIA, nimodipine, or ω-Agatoxin-IVA. The K+ channel blockers 4-aminopyridine (100 μm) and BaCl2 (300 μm) each reduced by 40–50% the inhibitory actions of WIN-2, and their effects were additive. These data suggest that CB1 receptors are located on the cortical afferents to the nucleus and can reduce glutamate synaptic transmission within the NAc by modulating K+ channels activity. ER -