Investigation of Lifelong Cognitive Impairments Following Perinatal and Perpubertal THC Exposure

围产期和青春期 THC 暴露后终身认知障碍的调查

• 批准号: 9377647
• 负责人: VINCENT P MARKOWSKI
• 金额: $ 37.32万
• 依托单位: COLLEGE AT GENESEO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9377647
• 关键词: Adolescence; Adolescent; Adolescent Development; Adult; Affect; Age; Agonist; Animal Testing; Animals; Attention; Attentional deficit; Behavior; Behavioral; Biological Assay; Birth; Blood; Brain; CNR1 gene; Cannabinoids; Cannabis; Child; Clinical; Cognitive; Cognitive deficits; Computer software; Consumption; Data; Development; Dose; Elderly; Executive Dysfunction; Exposure to; Female; Future; Glutamates; Goals; Hand Strength; Hippocampus (Brain); Human; Impaired cognition; Impairment; Infant; Investigation; Lactation; Lead; Learning; Legal; Life; Literature; Long-Term Effects; Longevity; Marijuana; Measures; Mediating; Medical Marijuana; Memory; Modeling; Motor; Motor Activity; Neurons; Neurotoxins; Neurotransmitters; Oral; Oral Administration; Perinatal; Perinatal Exposure; Placenta; Prefrontal Cortex; Pregnancy; Procedures; Psychotropic Drugs; Puberty; Rattus; Research; Rotarod Performance Test; Sampling; Series; Serum; Smoke; Social Behavior; Social Environment; Social Functioning; Staining method; Stains; Structure; System; THC exposure; Testing; Tetrahydrocannabinol; Time; Toxic effect; Tremor; United States; Weaning; Work; adolescent brain development; aged; axon growth; behavior test; behavioral impairment; brain tissue; cohort; critical period; dentate gyrus; design; developmental neurotoxicity; fetal; gamma-Aminobutyric Acid; juvenile animal; light microscopy; longitudinal analysis; male; middle age; migration; neuromechanism; offspring; peripubertal period; postnatal; pregnant; prenatal exposure; response; senescence; sex; social; subcutaneous; synaptogenesis; trend; young adult

Marijuana is a widely-used psychoactive substance, but its potency as a developmental neurotoxicant is poorly understood and little data on developmental exposure to marijuana has been collected. This data gap is alarming since marijuana consumption will increase in the United States as a consequence of the legalization trend. It is well known that the developing brain can be more sensitive to neurotoxicants than the adult brain. The impact of neurotoxicants on fetal brain development following maternal consumption of marijuana has only begun to be understood. Emerging clinical evidence indicates that prenatal exposure to marijuana is associated with tremors and exaggerated startles in infants and attention deficits and other executive dysfunctions in older children. The long-term effects of cannabinoids on adolescents is also not well understood. Adolescents could affect their own brains directly if they smoke marijuana during this second critical period of brain development. Since there is little or no data indicating whether early cannabinoid exposure in utero or during adolescence can produce latent toxicity that emerges later in life, the goal of the proposed research is to identify age, sex, and dose-specific effects of marijuana on cognitive behaviors and the brain structures that mediate them. The proposed research will identify the most sensitive, lifelong sex- specific behavioral deficits and cognitive impairments produced by the lowest dose exposure to marijuana, specifically to one cannabinoid, delta-9-tetrahydrocannabinol (THC), the principle psychoactive agent in marijuana that is known to cross the placenta and enter the developing brain during the perinatal and juvenile periods. A rat model of developmental THC exposure will be used to examine attention, learning, memory, motor, and social functions. Attention behaviors will be examined with the Go/no-go operant procedure. Learning and memory will be examined with operant procedures such as delayed spatial alternation. Motor function will be assessed with functional observation battery, open field exploration, grip strength and Rotarod tests. Social behavior will be measured with procedures using the 3-chamber sociability apparatus. Two cohorts of exposed rats will be used to examine different critical periods of brain development. For the perinatal cohort, rats will be gavaged with a daily oral dose of 0, 2, 5, or 10 mg/kg THC from gestation day 1 until weaning. For the peripubertal cohort, exposure to 0, 2, 7.5, or 15 mg/kg will begin immediately after weaning and continue throughout puberty (postnatal day 22-40). In each age cohort, male-female pairs of littermates will be assigned to one of three test ages: young adult (2-months), middle adult (12-months), and senescent (18-months). After the behavioral tests are completed, the GABA neurotransmitter system in the hippocampus and glutamate system in the prefrontal cortex will be examined histochemically. A third, smaller perinatal exposure cohort will be generated to provide blood and brain samples to determine THC and metabolite disposition following oral administration. Collectively, this data will fill a gap in the literature and provide information about the relationship between applied dose, disposition in the offspring, and long-term behavioral deficits.

大麻是一种广泛使用的精神活性物质，但它作为一种发育神经毒剂的效力很差 人们对此一无所知，而且几乎没有收集到有关发育过程中接触大麻的数据。这一数据差距是 令人担忧的是，由于大麻合法化，美国的大麻消费将增加 潮流。众所周知，发育中的大脑可能比成人大脑对神经毒物更敏感。 在母亲吸食大麻后，神经毒物对胎儿大脑发育的影响只有 开始被理解了。新出现的临床证据表明，产前接触大麻是 与婴儿的震颤和夸大的惊吓以及注意力缺陷和其他执行者有关 年龄较大的儿童出现功能障碍。大麻对青少年的长期影响也不是很好。 明白了。青少年如果在这一秒内吸食大麻，可能会直接影响自己的大脑。 大脑发育的关键时期。因为很少或根本没有数据表明早期的大麻素 在子宫或青春期暴露会产生潜在的毒性，并在以后的生活中出现，目标是 拟议的研究旨在确定大麻的年龄、性别和剂量对认知行为的特定影响，以及 调节它们的大脑结构。这项拟议的研究将确定最敏感、最终生的性行为-- 低剂量大麻暴露产生的特定行为缺陷和认知障碍， 特别是一种大麻素，三角洲-9-四氢大麻酚(THC)，它是 已知的在围产期和青少年时期穿过胎盘进入发育中的大脑的大麻 句号。一个发育中的THC暴露的大鼠模型将被用来检查注意力，学习，记忆， 运动和社交功能。注意行为将通过进行/不进行操作程序进行检查。 学习和记忆将通过可操作的程序进行检查，如延迟空间交替。马达 使用功能观察组、野外探险、握力和旋转棒来评估功能 测试。社会行为将通过使用三腔社交仪器的程序进行测量。二 暴露的大鼠队列将被用来检查大脑发育的不同关键时期。对于围产期的 队列，大鼠从妊娠第1天开始，每天给予0、2、5或10 mg/kg的THC灌胃 断奶了。对于青春期周围人群，在断奶后立即开始暴露于0、2、7.5或15毫克/公斤 并持续整个青春期(出生后第22-40天)。在每个年龄队列中，雄性和雌性配对产仔 将被分配到三个测试年龄中的一个：青年(2个月)、中年(12个月)和衰老 (18个月)。在行为测试完成后，海马区的GABA神经递质系统 前额叶皮质的谷氨酸系统将进行组织化学检查。第三个，较小的围产儿 将产生暴露队列，以提供血液和大脑样本，以确定THC和代谢物 口服给药后的处理。总而言之，这些数据将填补文献中的空白，并提供 关于应用剂量、在后代中的处置和长期行为之间的关系的信息 赤字。