Endocannabinoid modulation of memory

描述（由申请人提供）：发现脑中由大麻素CB 1受体和内源性大麻素（例如，anandamide和2-AG）已经引起了人们对理解该系统的生理功能的极大兴趣。基于体内和体外证据的汇聚，已经提出该系统在记忆随时间退化的基础过程中发挥积极作用（即，遗忘）以及对不再强化的习得行为的抑制（即，灭绝）。在正常情况下，这些过程被进一步假设为促进新信息的编码。本申请中提出的研究将通过永久地阻断内源性大麻素信号传导（即，CB 1（-/-）小鼠）或通过使用CB 1受体拮抗剂SR 141716急性给药。虽然这些方法可以间接地暗示内源性大麻素的参与，但其中脂肪酸酰胺水解酶（FAAH）（负责大麻素代谢的主要酶）已被遗传缺失的小鼠的可用性（即，FAAH（-/-）小鼠）沿着选择性FAAH抑制剂将使我们能够确定这种内源性大麻素是否在记忆中发挥作用。此外，我们将研究内源性大麻素调节记忆的神经底物和受体作用机制。我们将确定大麻素和2-AG的水平是否被发现在内源性大麻素音调下的行为程序所改变。最后，还将进行实验以确定大麻素的记忆效应是否在海马体中介导，海马体是一个不仅含有CB 1受体和内源性大麻素的大脑区域，而且已知在学习和记忆中发挥作用。总的来说，这些研究将进一步加深我们对该系统的生理功能的理解，并弥合内源性大麻素系统的体外和体内作用之间的差距。

DESCRIPTION (provided by applicant): The discovery of an endocannabinoid system in the brain consisting of cannabinoid CB1 receptors and endocannabinoids (e.g., anandamide and 2-AG) has generated a great deal of interest in understanding the physiological functions of this system. Based on converging in vivo and in vitro evidence this system has been proposed to play an active role in processes that underlie the degradation of memory over time (i.e., forgetting) as well as the suppression of learned behaviors that are no longer reinforced (i.e., extinction). Under normal circumstances, these processes are further hypothesized to facilitate the encoding of new information. The studies proposed in this application will examine the function of this system by blocking endocannabinoid signaling either permanently (i.e., CB1 (-/-) mice) or acutely through the use of the CB1 receptor antagonist SR 141716. Although these approaches can indirectly implicate the involvement of endocannabinoids, the availability of mice in which fatty acid amide hydrolase (FAAH), the primary enzyme responsible for anandamide metabolism, has been genetically deleted (i.e., FAAH (-/-) mice) along with a selective FAAH inhibitor will enable us to determine whether this endocannabinoid plays a role in memory. Additionally, we will investigate the neural substrates and receptor mechanisms of action that underlie endocannabinoid modulation of memory. We will ascertain whether the levels of anandamide and 2-AG are modified by behavioral procedures that are found to be under endocannabinoid tone. Finally experiments will also be conducted to determine whether the mnemonic effects of the cannabinoids are mediated in the hippocampus, a brain region that not only contains CB1 receptors and endocannabinoids, but also is known to play a role in learning and memory. Collectively, these studies will further our understanding of the physiological function of this system as well as bridge the gap between the in vitro and in vivo actions of the endocannabinoid system.