COGNITIVE AND NEUROCHEMICAL EFFECTS OF DELTA9-THC IN RATS

Delta9-THC 对大鼠的认知和神经化学影响

• 批准号: 7651321
• 负责人: LOREN H. PARSONS
• 金额: $ 19.53万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651321
• 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。长期大量使用大麻可能会导致 认知处理受损，其特征是注意力、记忆力、决策和 抑制性控制。对人类的神经成像研究表明，长期大量使用大麻 导致前额叶(眶前叶)皮质、海马体和 基底节，有人认为这些区域的神经功能障碍导致了 推动大麻持续使用的抑制性控制。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 采用啮齿动物行为测试来评估A9-四氢大麻酚(A9-TH)慢性治疗的效果。 A9-THC对青春期和成年大鼠认知功能的影响及A9-THC对大鼠认知功能的影响 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浓度与吸食人类大麻的人达到的浓度相当，将被给予 青春期和成年大鼠每14天重复一次，其中A9-THC每次2次 每天6天，然后是8天的无药期，在此期间进行行为测试。这 A9-THC剂量和行为测试的周期将重复长达6个月，行为测试将 在停止服用A9-THC后，继续服用两个月。在老鼠寿命的背景下，这将是 提供人类长期使用大麻的合理近似值。有针对性的实验 1将评估在A9-THC期间和之后认知功能障碍的发病、进展和持续性 给药方案。注意能力评估(5-CSRTT)、冲动选择/决策(延迟折扣 任务)、冲动动作/抑制控制(DRL测试)和执行功能(集合转移) 制造。在特定目标2中的实验将使用活体脑微透析来表征改变 与A9-THC相关的额叶皮质及相关区域的神经化学功能 在这些行为任务中的表现缺陷。与任务相关的单胺类物质间质水平的改变， 将比较兴奋性和抑制性氨基酸、乙酰胆碱和内源性大麻素。 治疗组之间的差异。这些啮齿动物实验将补充神经心理测试和 青春期非人灵长类、青春期人类和成人的脑成像 本中心的人文工程。这四个项目的建立将为我们提供非常强的科学性 大麻滥用的神经心理学和神经生物学基础调查平台 依赖。