Molecular sites of delta-9-THC actions on brain function

这个项目的启动是为了填补我们关于长期使用大麻对人类认知不良影响的神经生物学基础知识的空白。众所周知，人类急性和慢性使用大麻都会损害短期记忆、反应时间和一般的高阶认知处理。这些研究试图利用动物模型来探索急性和慢性暴露于大麻中的主要精神活性成分-德尔塔9-四氢大麻酚（THC）对海马和腹侧被盖区（VTA）神经生理学的影响。我们之前发表的研究表明，反复注射四氢大麻酚会阻断长期增强（LTP），这是一种与学习和记忆相关的细胞。此外，单次注射四氢大麻酚不足以阻断LTP，最后一次注射四氢大麻酚后LTP阻断持续3d，每次注射四氢大麻酚前用拮抗剂AM251 （2 mg/kg）预处理动物可以阻止LTP阻断。目前正在进行的其他实验将检验一种假设，即CB1大麻素受体对于生物体的正常认知、学习和记忆是必要的。在这些研究中，我们比较了不同年龄CB1+/+和-/-动物海马脑切片中LTP的水平。此外，我们正在使用全细胞记录来定义急性四氢大麻酚暴露对海马脑切片中单个神经元的作用。迄今为止，大多数研究都利用合成的CB1激动剂来评估CB1受体在调节海马突触功能中的作用。通过比较四氢大麻酚与这些合成激动剂的作用，我们希望确定四氢大麻酚的假定分子靶点，这可能有助于解释人类长期使用大麻后的记忆障碍。我们最近的研究发现，尽管THC在抑制海马中谷氨酸释放方面起到部分激动剂的作用，但当测量其对海马中GABA释放的抑制作用时，它是完全激动剂。我们认为这种差异是由于脑结构中gaba能轴突末端的CB1受体密度比谷氨酸末端高得多，我们提出这提供了强有力的证据，表明THC相互作用破坏海马依赖记忆的主要部位是gaba能系统。在另一项研究中，我们报道了大麻素对海马谷氨酸释放的影响，当腺苷A1受体被阻断时，大麻素对海马谷氨酸释放的影响可以大大增强。这表明内源性腺苷参与调节海马CB1受体的信号强度，内源性大麻素功能受腺苷系统控制。

This project was initiated to fill a void in our knowledge regarding the neurobiological substrates of the the adverse effects of chronic marijuana use on cognition in humans. It is well-known that both acute and chronic marijuana use in humans impairs short-term memory, reaction times, and general higher-order cognitive processing. These studies seek to utilize animal models to explore the effects of both acute and chronic exposure to the main psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC) on the neurophysiology of the hippocampus and now the ventral tegmanetal area (VTA). Our prior published study showed that repeated injections of THC blocked long-term potentiation (LTP), a cellular correlate of learning and memory. Furthermore, a single injection of THC was insufficient to block LTP, the LTP blockade persisted for 3d after the last THC injection, and it was prevented by pretreatment of the animals before each THC injection with the antagonist AM251 (2 mg/kg). Additional experiments now under way will examine the hypothesis that the CB1 cannabinoid receptor is necessary to permit normal cognition and learning and memory over the life span of an organism. For these studies, we are comparing the level of LTP in hippocampal brain slices obtained from CB1+/+ and -/- animals at various ages. In addition, we are defining the actions of acute THC exposure on individual neurons in hippocampal brain slices using whole-cell recordings. The majority of studies to date have utilized synthetic CB agonists to assess the role of CB1 receptors in modulating hippocampal synaptic function. By comparing the effects of THC to those of these synthetic agonists, we hope to identify putative molecular targets of THC that may help explain memory impairments in humans following chronic marijuana use. Our most recent work has found that whereas THC acts as a partial agonist in the inhibition of glutamate release in the hippocampus, it is a full agonist when its effects are measured on the inhibition of GABA release in the hippocampus. We believe that this difference is due to a much higher CB1 receptor density on GABAergic axon terminals versus glutamate terminals in this brain structure, and we have proposed that this provides strong evidence that the primary site of THC's interaction to disrupt hippocampal-dependent memory is on GABAergic systems. In a separate study that is in review, we have reported that the effects of cannabinoids on hippocampal glutamate release can be greatly potentiated when adenosine A1 receptors are blocked. This suggests that endogenous adenosine is involved in regulating the strength of signaling through CB1 receptors in the hippocampus, and that endocannabinoid function is under control of the adenosine system.