Cannabinoids in Early Sea Urchin Development

描述(由申请人提供)： 该项目符合NIDA/CEBRA标准，因为它提供了一种新的方法来评估怀孕早期接触滥用药物的潜在风险。该项目使用早期海胆胚胎作为模型系统，使用药物扰动和救援策略。这个动物模型代表了一个敏感的、高通量的生物传感器系统，用于筛选药物和神经毒物对早期胚胎发育的影响。 该项目调查了产前接触精神活性药物的影响，因为越来越多的证据表明，在神经系统出现之前，各种神经递质对于海胆胚胎的早期发育是必要的，而且有证据表明，这些功能是由受体和载体介导的转运体介导的，与哺乳动物神经系统中发现的类似。它侧重于大麻类化合物，因为1)以前的报道表明，这些物质在受精和小鼠早期发育中发挥作用，以及2)初步证据表明，大麻类化合物anandamide通过CB1受体和载体介导的转运蛋白调节早期海胆的发育。 具体目的是确定神经前大麻素系统的关键组成部分，包括受体和转运体，并利用免疫化学和生物化学方法描述这一系统的发育动态。我们将确定大麻素引起的细胞表型变化，并寻找潜在的解毒剂来防止它们，包括新的亲脂性大麻素受体拮抗剂。预计这些研究将为预防产前暴露大麻素的有害影响的潜在治疗策略提供见解。未来的研究将在小鼠身上测试这些治疗策略。

DESCRIPTION (provided by applicant): This project fulfills the NIDA/CEBRA criteria because it provides a novel approach to evaluate potential risks of exposure to drugs of abuse during early pregnancy. The project utilizes early sea urchin embryos as a model system, using a pharmacologic perturb-and-rescue strategy. This animal model represents a sensitive, high-throughput biosensor system for screening effects of drugs and neurotoxicants on early embryonic development. The project investigates effects of prenatal exposure to psychoactive drugs because of accumulated evidence that a variety of neurotransmitters are necessary for early development of sea urchin embryos, prior to the appearance of a nervous system ("pre-nervous neurotransmitters"), and evidence that these functions are mediated by receptors and carrier-mediated transporters similar to those found in the mammalian nervous system. It focuses on cannabinoids because of 1) previous reports that these substances play roles in fertilization and early mouse development, and 2) preliminary evidence that the cannabinoid, anandamide regulates early sea urchin development, mediated by CB1 receptors and carrier mediated transporters. The Specific Aims are designed to identify key components of the pre-nervous cannabinoid system, including receptors and transporters, and to characterize developmental dynamics of this system, using immunochemical and biochemical approaches. We will determine cell phenotype changes evoked by cannabinoids and search for potential antidotes to prevent them, including new lipophilic cannabinoid receptor antagonists. It is anticipated that these studies will provide insights into potential therapeutic strategies to prevent deleterious effects of prenatal cannabinoid exposure. Future studies will test these therapeutic strategies in the mouse.