COGNITIVE AND NEUROCHEMICAL EFFECTS OF DELTA9-TETRAHYDROCANNABINOL IN RATS

大麻是美国最常用的非法药物。长期大量使用大麻可能导致 在以注意力、记忆力、决策能力和 抑制控制人类神经影像学研究表明，长期大量使用大麻 产生前额叶（眶额）皮质、海马和脑区成分功能的改变。 基底神经节，并且已经提出，这些区域的神经功能障碍导致神经元的丧失。 抑制控制，推动继续使用大麻。然而，细胞和神经化学机制 大麻引起的认知功能障碍的原因尚不清楚。该项目的总体目标是 使用啮齿动物行为任务来评估用Δ 9-四氢大麻酚（Δ 9-tetrahydrocannabinol，Δ 9-tetrahydrocannabinol）长期治疗的效果。 THC）对青少年和成年大鼠认知功能的影响，并表征A9-THC诱导的 这些行为异常背后的神经化学信号。产生血浆的A9-THC剂量 A9-THC浓度将包括人类大麻吸烟者所达到的浓度， 在14天区组的重复周期中，在青春期和成年大鼠中， 每天6天，然后是8天的无药物期，在此期间进行行为测试。这 A9-THC给药和行为测试的循环将重复长达6个月，并且行为测试将 在停止A9-THC给药后持续长达两个月。在老鼠寿命的背景下， 提供了人类长期使用大麻的合理近似值。具体目标的实验 1将评估A9-THC期间和之后认知功能障碍的发作、进展和持续性 给药方案。注意力能力（5-CSRTT）、冲动选择/决策（延迟折扣） 任务），冲动行动/抑制控制（DRL测试）和执行功能（设置转移）将被 进行了具体目标2中的实验将采用体内脑微透析来表征改变的脑组织。 额叶皮层和与A9-THC诱导的脑损伤相关的相关区域中的神经化学功能 在这些行为任务中的表现缺陷。单胺间质水平的任务相关改变， 将比较兴奋性和抑制性氨基酸、乙酰胆碱和内源性大麻素 治疗组之间。这些啮齿动物实验将补充神经心理学测试， 在青春期非人灵长类动物、青少年和成人中进行脑成像 这个中心的人类项目。这四个项目的建立，将提供很强的科学性 研究滥用大麻的神经心理学和神经生物学基础的平台， 依赖

Cannabis is the most commonly used illicit drug in the United States. Chronic heavy cannabis use can result in impaired cognitive processing as characterized by deficits in attention, memory, decision-making and inhibitory control. Neuroimaging studies in humans have demonstrated that long-term heavy cannabis use produces alterations in the function of the prefrontal (orbitofrontal) cortex, hippocampus and components of the basal ganglia, and it has been proposed that neural dysfunction in these regions contributes to a loss of inhibitory control that propels continued cannabis use. However, the cellular and neurochemical mechanisms that underlie cannabis-induced cognitive dysfunction are not known. The overall goals of this project are to employ rodent behavioral tasks to evaluate the effect of chronic treatment with A9-tetrahydrocannabinol (A9- THC) on cognitive function in adolescent and adult rats and to characterize A9-THC-induced alterations in neurochemical signaling that underlie these behavioral abnormalities. A9-THC doses that produce plasma A9-THC concentrations which bracket those achieved by human cannabis smokers will be administered to periadolescent and adult rats in a repeating cycle of 14-day blocks in which A9-THC is administered 2x per day for 6 days, followed by an 8-day drug-free period in during which behavioral testing is performed. This cycle of A9-THC dosing and behavioral testing will be repeated for up to 6 months, and behavioral testing will continue for up to two months after cessation of A9-THC dosing. In the context of the rat lifespan this will provide a reasonable approximation of long-term cannabis use in humans. The experiments in Specific Aim 1 will evaluate the onset, progression and persistence of cognitive dysfunction during and after this A9-THC dosing regimen. Evaluations of attentional capacity (5-CSRTT), impulsive choice/decision making (delaydiscount task), impulsive action/inhibitory control (DRL testing) and executive function (set-shifting) will be made. The experiments in Specific Aim 2 will employ in vivo brain microdialysis to characterize altered neurochemical function in the frontal cortex and related areas that are associated with A9-THC-induced performance deficits in these behavioral tasks. Task-related alterations in interstitial levels of monoamines, excitatory and inhibitory amino acids, acetylcholine and endogenous cannabinoids will be compared between treatment groups. These rodent experiments will complement the neuropsychological testing and brain imaging to be performed in the periadolescent non-human primate, adolescent human and adult human projects of this Center. The establishment of these four, projects will provide a very strong scientific platform for investigations into the neuropsychological and neurobiological bases of cannabis abuse and dependence.