The Functional Neurobiology of Cannabinoids in Brain

大麻（大麻）是美国最广泛使用的非法滥用药物，这种药物的活性成分，其中包括delta 9-tetrahydrocannabinol（THC），统称为大麻素（CB）。在过去的十年中，包括特定CB受体的克隆和这些受体的内源性激动剂的鉴定在内的一些科学进展，提供了一个机会来评估CB系统在急性和长期CB暴露期间调节神经元活性的功能。CB受体激活的主要后果之一是哺乳动物脑中主要抑制性（GABA）和兴奋性（谷氨酸）氨基酸神经递质的突触前抑制。我们自己发表的和初步的数据检查CB行动在脑切片表明，CB受体激活引起一个明显的抑制GABA能突触传递在海马和丘脑核。海马体中的这些效应可能至少部分地导致了吸食大麻引起的众所周知的短期记忆中断，而在脑桥核中观察到的直接效应可能至少是这种药物的一些奖励或愉悦特性的原因，这些特性被认为可以维持其在人类中的使用。因此，建议中描述的实验的目的是了解CB药物作用于改变CNS功能的神经生物学底物，特别强调在这两个相关脑区中突触传递的调节。为此，这些研究将确定CB改变这些特定神经元回路中突触传递的分子机制，将确定内源性CB在调节神经元活动中发挥的作用，并将确定CB耐受性和依赖性的生理相关性是否可以确定，以便我们可以进一步了解长期大麻暴露的神经生物学后果。这些实验将利用电生理技术，结合微分干涉显微镜来识别活体脑切片中的特定神经元。然后，我们将进行研究与几个最近开发的药理学药物，破坏内源性CB catalysts和神经元的再摄取。此外，单细胞解剖技术将被纳入这些研究，使参与这些相互作用的神经元可以最终确定基于形态学和组织化学特征。这些研究将显著增加我们对CB神经生物学的理解，并将提供与理解人类长期接触CB的细胞后果相关的信息。

Marijuana (Cannabis sativa) is the most widely used illegal drug of abuse in the U.S. The active ingredients of this drug, which include delta9-tetrahydrocannabinol (THC), are collectively known as cannabinoids (CBs). Several scientific advances in the last decade, including the cloning of specific CB receptors, and the identification of endogenous agonists for these receptors, provide an opportunity to evaluate the function of the CB system in regulating neuronal activity both acutely, and during long-term CB exposure. One of the primary consequences of CB receptor activation is the presynaptic inhibition of the major inhibitory (GABA) and excitatory (glutamate) amino acid neurotransmitters in the mammalian brain. Our own published and preliminary data examining CB actions in brain slices suggest that CB receptor activation causes a pronounced inhibition of GABAergic synaptic transmission in both the hippocampus and the nucleus accumbens. These effects in the hippocampus may be at least partly responsible for the well-known disruption of short-term memory caused by marijuana consumption, whereas the direct effects observed in the nucleus accumbens may be responsible for at least some of the rewarding or pleasurable properties of this drug that are presumed to sustain its use in humans. The goal of the experiments described in thus proposal is to understand the neurobiological substrates upon which CB drugs act to alter CNS function, with particular emphasis on the modulation of synaptic transmission: in these two relevant brain: areas. To this end, these studies will identify the molecular mechanisms through which CBs alter synaptic transmission in these specific neuronal circuits, will determine what role endogenously occurring CBs play in regulating neuronal activity, and will establish whether physiological correlates of CB tolerance and dependence can be identified so that we may further understand the neurobiological consequences of long-term marijuana exposure. These experiments will utilize electrophysiological techniques, combined with differential interference microscopy to identify specific neurons in living brain slices. We will then conduct studies with several recently developed pharmacological agents that disrupt endogenous CB catabolism and re-uptake by neurons. In addition, single-cell anatomical techniques will be incorporated into these studies so that the neurons involved in these interactions can be conclusively identified based upon morphological and histochemical features. These studies will significantly increase our understanding of the neurobiology of CBs, and will provide information that should prove relevant to understanding the cellular consequences of long-term CB exposure in humans.