COGNITIVE AND NEUROCHEMICAL EFFECTS OF DELTA9-TETRAHYDROCANNABINOL IN RATS

Delta9-四氢大麻酚对大鼠的认知和神经化学影响

• 批准号: 7390050
• 负责人: LOREN H. PARSONS
• 金额: $ 20.42万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390050
• 关键词: Acetylcholine; Adolescent; Adult; Amino Acids; Area; Attention; Basal Ganglia; Behavioral; Brain; Brain imaging; Cannabinoids; Cannabis; Cannabis Abuse; Choice Behavior; Chronic; Cognitive; Complement; Data; Decision Making; Dependence; Dose; Endocannabinoids; Evaluation; Functional disorder; Goals; Hippocampus (Brain); Human; Illicit Drugs; Impaired cognition; Investigation; Longevity; Memory; Microdialysis; Neurobiology; Neuropsychological Tests; Performance; Pharmaceutical Preparations; Plasma; Process; Rattus; Relative (related person); Rodent; Rodent Model; Signal Transduction; Smoker; Testing; Tetrahydrocannabinol; Treatment Protocols; United States; base; behavior test; cognitive function; day; executive function; frontal lobe; in vivo; interstitial; monoamine; neurochemistry; neuroimaging; neuropsychological; nonhuman primate; relating to nervous system; research study

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.

大麻是美国最常用的非法药物。长期大量使用大麻会导致 认知处理受损，其特征是注意力、记忆力、决策和 抑制控制。人类神经影像学研究表明，长期大量使用大麻 导致前额叶（眶额）皮层、海马体和各组成部分的功能发生改变 基底神经节，有人提出这些区域的神经功能障碍会导致 抑制控制推动大麻的持续使用。然而，细胞和神经化学机制 大麻引起的认知功能障碍背后的原因尚不清楚。该项目的总体目标是 采用啮齿动物行为任务来评估 A9-四氢大麻酚（A9- THC）对青少年和成年大鼠认知功能的影响，并表征 A9-THC 诱导的认知功能改变 这些行为异常背后的神经化学信号传导。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 青春期和成年大鼠以 14 天为一个重复周期，每次给予 2 次 A9-THC 为期 6 天，然后是 8 天的禁药期，在此期间进行行为测试。这 A9-THC 给药和行为测试的周期将重复长达 6 个月，并且行为测试将 停止服用 A9-THC 后，可继续服用长达两个月。在大鼠寿命的背景下，这将 提供人类长期使用大麻的合理近似值。具体目标中的实验 1 将评估 A9-THC 期间和之后认知功能障碍的发生、进展和持续性 给药方案。注意力能力评估（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（设定转移） 制成。具体目标 2 中的实验将采用体内脑微透析来表征改变的 与 A9-THC 诱导相关的额叶皮层和相关区域的神经化学功能 这些行为任务中的表现缺陷。与任务相关的单胺间质水平的改变， 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和 对青春期非人类灵长类动物、青少年人类和成人进行脑成像 该中心的人类项目。这四个项目的建立，将为我们提供非常有力的科学依据。 调查大麻滥用的神经心理学和神经生物学基础的平台 依赖性。