Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus

Psychoactive effects of cannabinoids are thought to be mediated, at least i n part, by suppression of both glutamate and GABA release via CB1 cannabino id receptor. Two types of cannabinoid receptor (CB1 and CB2) have been clon ed so far. The CB1 receptors are abundantly expressed in the nervous system , whereas CB2 receptors are limited to lymphoid organs (Matsuda et al., 199 0; Munro et al., 1993). Immunocytochemical and electrophysiological studies revealed that in the hippocampus CB1 receptors are expressed on axon termi nals of GABAergic inhibitory interneurons (Tsou et al., 1999; Katona et al. , 1999) and activation of these receptors decreases GABA release (Hajos et al., 2000). Other physiological studies pointed out the involvement of CB1 receptors in the modulation of hippocampal glutamatergic synaptic transmiss ion and long-term potentiation (Stella et al., 1997; Misner and Sullivan, 1 999), but anatomical studies could not confirm the existence of CB1 recepto rs on glutamatergic terminals. Here we examined cannabinoid actions on both glutamatergic and GABAergic synaptic transmission in the hippocampus of wi ld type (CB1+/+) and CB1 receptor knockout mice (CB1-/-). The synthetic can nabinoid agonist WIN55,212-2 reduced the amplitudes of excitatory postsynap tic currents in both wild type and CB1-/-mice, while inhibitory postsynapti c currents were decreased only in wild type mice, but not in CB1-/- animals . Our findings are consistent with a CB1 cannabinoid receptor-dependent mod ulation of GABAergie postsynaptic currents, but a novel cannabinoid-sensiti ve receptor must be responsible for the inhibition of glutamatergic. neurot ransmission. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights r eserved.