Endocannabinoids and the Control Of Behavior and Cardiovascular Function

早些时候，我们使用两瓶/自由选择范式的小鼠模型首次证明了通过CB1受体作用的内源性大麻素以一种年龄相关的方式促进自愿饮酒(PNAS 100：1393,2003)。这项研究中使用的脑穿透性CB1反向激动剂利莫那班随后被引入用于治疗肥胖症，但由于神经精神副作用，包括焦虑、抑郁和自杀念头，不得不在2008年从药品市场撤出。我的实验室倡导的另一种方法是引入外周受限的CB1反向激动剂，这种药物保留了利莫那班的代谢功效，但在代谢综合征的啮齿动物模型中没有神经行为影响。矛盾的是，这类化合物还被发现可以减少食物摄入量，这是一种中央调节效应。在饮食诱导的肥胖小鼠中，外周阻断CB1可以通过抑制脂肪组织中瘦素的产生和增加肾脏中瘦素的清除来逆转其高瘦素血症，从而迅速逆转其瘦素抵抗，从而解决了这一悖论。这让我们想知道，C57BL6小鼠的高酒精偏好是否也可能通过阻断外周CB1而间接影响到CB1激活所促进的另一种中枢功能。一种可能的机制与Ghrelin有关，这是一种胃肽，通过大脑中的Ghrelin受体促进食欲。初步实验表明，利莫那班和两种非脑穿透性CB1反向激动剂JD5037和我们自己的化合物MRI-1569在显著减少C57BL6小鼠的总酒精摄入量和乙醇偏好方面等效，采用两瓶自由选择范例。此外，阻断CB1可显著降低血浆总生长激素水平和乙酰化生长激素水平。我们现在正在测试这些化合物在Ghrelin基因敲除小鼠和Ghrelin受体基因敲除小鼠中的效果，这些小鼠是从Scripps的Roy G Smith获得的。我们还在测试CB1对离体胃制剂中Ghrelin释放的调节。这些化合物还在与Dr合作的操作饮酒范例中进行了测试。安德鲁·霍姆斯。

We have earlier demonstrated for the first time that endocannabinoids acting via CB1 receptors promote voluntary alcohol drinking in an age-dependent manner, using a mouse model of two bottle/free choice paradigm(PNAS 100:1393, 2003. The brain-penetrant CB1 inverse agonist rimonabant used in this study was subsequently introduced as a treatment of obesity, but had to be wihdrawn from the pharmaceutical market in 2008, due to neuropsychiatric side effects, including anxiety, depression and suicidal ideation. An alternative approach, championed by my laboratory, was the introduction of peripherally restricted CB1 inverse agonists that retained the metabolic efficacy of rimonabant but were devoid of its neurobehavioral effects in rodent models of the metabolic syndrome. Paradoxically, such compounds were also found to reduce food intake, a centrally mediated effect. This paradox was resolved by the demonstration that peripheral CB1 blockade in diet-induced obese mice rapidly reversed their leptin resistance by reversing their hyperleptinemia, via inhibiting leptin production in adipose tissue and increasing leptin clearance in the kidney. This made us to wonder whether the high alcohol preference of C57Bl6 mice, another central function promoted by CB1 activation, may also be affected indirectly through blockade of CB1 in the periphery. A possible mechanism involves ghrelin, a gastric peptide that promotes appetite via ghrelin receptors in the brain. Preliminary experiments indicate that rimonabant and two non brain-penetrant CB1 inverse agonists, JD5037 and our own compound MRI-1569, were equieffective in markedly reducing total alcohol intake as well as ethanol preference in C57BL6 mice, using a two bottle, free choice paradigm. Furthermore, CB1 blockade significantly reduced plasma levels of total as well as acetylated ghrelin. We are now testing the effects of these compounds in ghrelin knockout as well as ghrelin receptor knockout mice obtained from Roy G Smith at Scripps. We are also testing CB1 regulation of ghrelin release in isolated stomach preparations. The compounds are also tested in an operant drinking paradigm in collaboration with dr. Andrew Holmes.