The inhibitory action of exo- and endocannabinoids on [3H]GABA release are mediated by both CB1 and CB2 receptors in the mouse hippocampus

Exogenous and endogenous cannabinoids play an important role in modulating the release of neurotransmitters in hippocampal excitatory and inhibitory networks, thus having profound effect on higher cognitive and emotional functions such as learning and memory. In this study we have studied the effect of cannabinoid agonists on the potassium depolarization-evoked [3H]GABA release from hippocampal synaptosomes in the wild-type (WT) and cannabinoid 1 receptor (CB1R)-null mutant mice.All tested cannabinoid agonists (WIN55,212-2, CP55,940, HU-210, 2-arachidonoyl-glycerol, 2-AG; delta-9-tetra-hydrocannabinol, THC) inhibited [3H]GABA release in WT mice with the following rank order of agonist potency: HU-210 > CP55,490 > WIN55,212-2 >> 2-AG > THC. By contrast, 2-AG and THC displayed the greatest efficacy eliciting almost complete inhibition of evoked [3H]GABA efflux, whereas the maximal inhibition obtained by HU-210, CP55,490, and WIN55,212-2 were less, eliciting not more than 40% inhibition. The inhibitory effect of WIN55,212-2, THC and 2-AG on evoked [3H]GABA efflux was antagonized by the CB1 receptor inverse agonist AM251 (0.5 μM) in the WT mice. In the CB1R knockout mice the inhibitory effects of all three agonists were attenuated. In these mice, AM251 did not antagonize, but further reduced the [3H]GABA release in the presence of the synthetic agonist WIN55,212-2. By contrast, the concentration-dependent inhibitory effects of THC and 2-AG were partially antagonized by AM251 in the absence of CB1 receptors. Finally, the inhibition of evoked [3H]GABA efflux by THC and 2-AG was also partially attenuated by AM630 (1 μM), the CB2 receptor-selective antagonist, both in WT and CB1 knockout mice.Our data prove the involvement of CB1 receptors in the effect of exo- and endocannabinoids on GABA efflux from hippocampal nerve terminals. In addition, in the effect of the exocannabinoid THC and the endocannabinoid 2-AG, non-CB1, probably CB2-like receptors are also involved.

► Natural, synthetic and endocannabinoids all inhibit GABA release from hippocampal nerve terminals. ► The effects of agonists are reversed by the CB1 antagonist AM251. ► The effects of agonists are partially retained in CB1 receptor knockout mice. ► The effect of THC and 2-AG are also reversed by the CB2 antagonist AM630.