Cannabinoid regulation of glycogen synthase kinase-3

大麻是目前美国最常用的非法药物。吸食大麻， 尤其是青少年，增加了在晚年发展为精神分裂样精神病的风险。在……里面 此外，患有双相情感障碍的人一生中使用大麻的流行率为20%-40%，而美国为6%。 普通民众。这些和其他流行病学数据表明，使用大麻易患上 易患精神疾病的人。糖原合成酶激酶3(GSK-3)是 GSK-3是边缘脑中一种重要的调节蛋白；GSK-3的过度活性与两者有关 躁郁症和精神分裂症。GSK-3被包括Akt在内的蛋白激酶磷酸化和失活 它是几种神经递质的下游组成部分，与情绪调节和精神病有关。 这项提案中提出的数据表明，通过延长大麻素-1受体(CB1R)的激活 大麻成分9-四氢大麻酚(THC)显著降低GSK-3的磷酸化 神经元。由于GSK-3的活性通过磷酸化而降低，这些数据与增强的GSK-3一致 接触THC后的活动。另一种CB1R激动剂CP55940与THC具有相同的作用。这些 初步数据与文献中有关D2多巴胺受体信号转导的数据一起用于 提出CB1R长时间激活导致ss-arrestin；ss-arrestin募集的假设 作为一种支架蛋白，使Akt与蛋白磷酸酶PP2A接近。AKT是 去磷酸化和失活，导致GSK-3活性的失调抑制。由于葛兰素史克-3过度活跃 与情绪调节失调和精神病有关，这些数据导致了这样的假设：THC介导 GSK-3活性的增加有助于大麻使用和精神疾病之间的关系。这个 当前项目的目标是检验CB1R介导的GSK-3激活的特定假设 通过ss-arrestin介导的对Akt的抑制而发生；是大脑区域特有的，与引起焦虑有关 以及THC和其他大麻素激动剂的压力增强作用。本项目的具体目标是：(1) 确定CB1R激动剂改变原代培养的GSK-3磷酸化状态的机制 (2)确定CB1R激动剂和CB1R激动剂对小鼠急性和慢性暴露的影响； 拮抗剂对脑区Akt和GSK-3的磷酸化和活性的影响 边缘系统：(3)确定SS-arrestin在CB1R激动剂和拮抗剂作用中的作用。 通过比较野生型和ss-arrestin-2缺失小鼠对焦虑和压力的行为分析。 成功完成这项建议中概述的研究将推进我们确定以下长期目标： 暴露大麻使个人容易患上精神疾病的机制。

Cannabis sativa is currently the most commonly-used, illicit drug in the United States. Cannabis use, particularly by adolescents, increases the risk of developing schizophrenia-like psychoses in later life. In addition, people with bipolar disorder have a 20-40% lifetime prevalence of cannabis use, compared to 6% in the general population. These and other epidemiological data demonstrate that cannabis use predisposes susceptible individuals to the development of psychiatric disorders. Glycogen synthase kinase 3 (GSK-3) is emerging as an important regulatory kinase in the limbic brain; over-activity of GSK-3 has been linked to both bipolar disorder and schizophrenia. GSK-3 is phosphorylated and inactivated by protein kinases, including Akt and is a down-stream component of several neurotransmitters involved in mood regulation and psychosis. Data presented in this proposal demonstrate that prolonged cannabinoid-1 receptor (CB1R) activation by the cannabis constituent, 9-tetrahydrocannabinol (THC), significantly decreases GSK-3 phosphorylation in neurons. Since GSK-3 activity is reduced by phosphorylation, these data are consistent with enhanced GSK-3 activity following THC exposure. A second CB1R agonist, CP55940 shared these effects of THC. These preliminary data, together with data in the literature regarding D2 dopamine receptor signaling, were used to formulate the hypothesis that prolonged CB1R activation results in recruitment of ss-arrestin; ss-arrestin functions as a scaffold protein, bringing Akt in proximity with the protein phosphatase, PP2A. Akt is dephosphorylated and inactivated, resulting in dysinhibition of GSK-3 activity. Since GSK-3 over-activity is associated with mood dysregulation and psychosis, these data lead to the hypothesis that THC-mediated increase in GSK-3 activity contributes to the relationship between cannabis use and psychiatric disorders. The objective of the current project is to test the specific hypothesis that CB1R-mediated activation of GSK-3 occurs through ss-arrestin-mediated inhibition of Akt; is brain region specific and contributes to the anxiogenic and stress-enhancing effects of THC and other cannabinoid agonists. The specific aims of this project are: (1) to determine the mechanism by which CB1R agonists alter the phosphorylation state of GSK-3 in primary neurons in culture; (2) the determine the effects of acute and chronic exposure of mice to CB1R agonists and antagonists on the phosphorylation and activities of Akt and GSK-3 in brain regions, particularly those of the limbic system: (3) to determine the role of ss-arrestin in the effects of CB1R agonists and antagonists in behavioral assays of anxiety and stress by comparing their effects in wild type and ss-arrestin-2 null mice. Successful completion of the studies outlined in this proposal will advance our long-term objective to determine the mechanisms by which cannabis exposure predisposes individuals to the development of psychiatric illness.