CB1 receptor-dependent and -independent inhibition of excitatory postsynaptic currents in the hippocampus by WIN 55,212-2

NEUROPHARMACOLOGY

卷:54

Article

Nemeth, Beata¹  Ledent, Catherine²  Freund, Tamas F.¹  Hajos, Norbert¹ 

[1] Hungarian Acad Sci, Inst Expt Med, H-1450 Budapest, Hungary

[2] Univ Libre Bruxelles, Inst Rech Interdisciplinarie Biol Humaine & Mol, B-1070 Brussels, Belgium

关键词: brain slices;    glutamate;    transmitter release;    hippocampus;    pyramidal cell;    cannabinoids;   

DOI  :  10.1016/j.neuropharm.2007.07.003

来源: Elsevier

【 摘 要 】

We investigated the effect of a synthetic cannabinoid, WIN 55,212-2 on excitatory postsynaptic currents (EPSCs) evoked by stimulation of Schaffer collaterals in CA1 pyramidal cells. Bath application of WIN 55,212-2 reduced the amplitude of EPSCs in dose-dependent manner tested between 0.01 nM and 30 mu M. In rats and mice, this cannabinoid ligand inhibited excitatory synapses in two steps at the nM and mu M concentrations. When the function of CB1 cannabinoid receptors (CB1R) was impaired, either by the application of a CB1R antagonist AM251, or by using CB1R knockout mice, WIN 55,212-2 in mu M concentrations could still significantly reduced the amplitude of EPSCs. WIN 55,212-2 likely affected the efficacy of excitatory transmission only at presynaptic sites, since both at low and high doses the paired pulse ratio of EPSC amplitude was significantly increased. The inactive enantiomer, WIN 55,212-3, mimicked the effect of WIN 55,212-2 applied in high doses. In further experiments we found that the CB1R-independent effect of 10 mu M WIN 55,212-2 at glutamatergic synapses was fully abolished, when slices were pre-treated with omega-conotoxin GVIA, but not with omega-agatoxin IVA. These data suggest that, in the hippocampus, WIN 55,212-2 reduces glutamate release from Schaffer collaterals solely via CB(1)Rs in the nM concentration range, whereas in mu M concentrations, WIN 55,212-2 suppresses excitatory transmission, in addition to activation of CB(1)Rs, by directly blocking N-type voltage-gated Ca2+ channels independent of CB(1)Rs. (c) 2007 Elsevier Ltd. All rights reserved.

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