Modulation of the exocytotic and carrier-mediated transmitter release by endogenous and exogenously added cannabinoids

大麻素CB 1受体抑制神经元中动作电位驱动的胞吐递质释放。利莫那班是一种逆CB 1激动剂，促进递质释放，可能是由于内源性大麻素如大麻素和/或2-花生四烯酸甘油建立的内源性音调中断。应通过测定海马切片（i）暴露于内源性大麻素合成和降解抑制剂或（ii）从不表达此类酶的小鼠中获得的海马切片中的递质释放来阐明其作用。利莫那班的易化作用也可能是由于CB 1受体具有组成性活性。这应通过比较CB 1受体的反向激动剂和中性拮抗剂对分离组织和细胞中递质释放的影响来检查。最后，几乎没有关于CB 1受体是否影响由缺氧引起的非胞吐性谷氨酸释放的信息。应在野生型小鼠和不表达CB 1受体或内源性大麻素合成或降解酶的小鼠的海马切片中研究此类受体的发生和可能的内源性张力。这些发现可能有助于更好地了解利莫那班的临床效果和CB 1激动剂作为神经保护药物的可能用途。

Cannabinoid CB1 receptors inhibit the action potential-driven, exocytotic transmitter release in neurons. Rimonabant, an inverse CB1 agonist, facilitates transmitter release, probably due to interruption of an endogenous tone built up by endocannabinoids like anandamide and/or 2-arachidonoylglycerol. Their role shall be clarified by determination of transmitter release in hippocampal slices (i) exposed to inhibitors of the synthesis and degradation of either endocannabinoid or (ii) obtained from mice not expressing such enzymes. The facilitatory effect of rimonabant might also be due to the fact that the CB1 receptors are constitutively active. This shall be checked by comparing the effect of an inverse agonist and neutral antagonist at CB1 receptors on transmitter release in isolated tissues and in cells. Finally, there is almost no information as to whether CB1 receptors affect the non-exocytotic glutamate release caused by hypoxia. The occurrence of such receptors and a possible endogenous tone shall be studied in hippocampal slices from wild type mice and mice not expressing CB1 receptors or endocannabinoid-synthesizing or -degrading enzymes. The findings may contribute to a better understanding of the clinical effect of rimonabant and of the possible use of CB1 agonists as neuroprotective drugs.