The Functional Neurobiology of Cannabinoids in Brain

大麻是美国使用最广泛的非法滥用药物。这种药物的有效成分，包括Delta9-四氢大麻酚(THC)，统称为大麻素(CBS)。过去十年的一些科学进展，包括克隆特定的CB受体，以及鉴定这些受体的内源性激动剂，为评估CB系统在急性和长期CB暴露期间调节神经元活动的功能提供了机会。CB受体激活的主要后果之一是哺乳动物大脑中的主要抑制性(GABA)和兴奋性(谷氨酸)氨基酸神经递质在突触前受到抑制。我们自己发表的研究CB在脑片中作用的初步数据表明，CB受体的激活导致海马和伏隔核中GABA能突触传递的明显抑制。海马体中的这些效应可能至少部分是众所周知的吸食大麻导致的短期记忆中断的原因，而在伏隔核观察到的直接效应可能至少是这种药物的一些有益或愉悦特性的原因，这些特性被认为是维持其在人类身上的使用。该提案中描述的实验的目标是了解CB药物改变中枢神经系统功能的神经生物学基础，特别是突触传递的调节：在这两个相关的大脑区域。为此，这些研究将确定CBS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CBS在调节神经元活动中所起的作用，并将确定是否可以确定CB耐受和依赖的生理关联，以便我们进一步了解长期接触大麻的神经生物学后果。这些实验将利用电生理学技术，结合差示干涉显微镜来识别活着的脑片中的特定神经元。然后，我们将用几种最近开发的药物进行研究，这些药物可以扰乱内源性CB的分解代谢和神经元的重新摄取。此外，单细胞解剖学技术将被纳入这些研究中，以便根据形态和组织化学特征最终确定参与这些相互作用的神经元。这些研究将显著增加我们对CBS神经生物学的理解，并将提供与理解长期接触CB在人类体内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.