Aberrant prefrontal cortical plasticity and neurobehavioral consequences of adolescent marijuana

青少年大麻异常的前额皮质可塑性和神经行为后果

• 批准号: 9981716
• 负责人: VIRGINIA M PICKEL
• 金额: $ 40.26万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981716
• 关键词: 2-arachidonylglycerol; Adolescence; Adolescent; Adult; Applications Grants; Behavioral; Brain; Brain region; CNR1 gene; Calcium; Cannabinol; Cholinergic Receptors; Chronic; Cognitive; Coupled; Diglycerides; Dopamine; Dose; Down-Regulation; Electrons; Emotional; Endocannabinoids; Female; Functional disorder; Generations; Genetic; Glutamate Receptor; Glutamates; Health; Human; Impaired cognition; Impairment; Individual; Inositol; Interneurons; Knowledge; Learning; Left; Marijuana; Marijuana Abuse; Mediating; Mediator of activation protein; Membrane Potentials; Memory impairment; Mental Depression; Mental disorders; Microscopic; Molecular Target; Mus; Muscarinic Acetylcholine Receptor; Muscarinic M1 Receptor; Muscarinics; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor A1; Neurons; Output; Patients; Pharmaceutical Preparations; Pharmacology; Prefrontal Cortex; Presynaptic Terminals; Process; Production; Psychotropic Drugs; Pyramidal Cells; Receptor Activation; Research; Rest; Risk; Role; Sex Differences; Short-Term Memory; Signal Transduction; Signaling Molecule; Surface; Synapses; Synaptic Membranes; Synaptic plasticity; System; Teenagers; Testing; Tetrahydrocannabinol; Transgenic Mice; Wild Type Mouse; behavior test; cognitive function; endogenous cannabinoid system; experience; in vivo; interdisciplinary approach; long term memory; male; marijuana use; mutant; neurobehavioral; postnatal; prevent; psychiatric symptom; receptor; receptor expression; receptor function; relating to nervous system; sex; social attention; social deficits; transcription factor

The escalation in recreational use of marijuana by today’s teenagers is a major health concern, because of the increased risk for psychiatric disorders in individuals who abuse marijuana during adolescence. The psychiatric symptoms include abnormalities in cognitive functions that are mediated largely through the prefrontal cortex (PFC) and associated limbic brain regions. Both pyramidal cells and interneurons in the PFC express cannabinoid-1 receptors (CB1Rs) that are activated by endocannabinoids and by Δ9-tetrahydro- cannabinol (Δ9-THC), the major psychoactive compound in marijuana. Chronic activation of these receptors by Δ9-THC downregulates the endocannabinoid system that is a key regulator of experience-dependent learning in the still immature PFC of adolescence. This learning is triggered by calcium influx through glutamatergic NMDA receptors comprised of subunits that are physically and functionally coupled to dopamine D1-like receptors (D1Rs). Pyramidal cells expressing D1Rs are among the PFC neurons most implicated in controlling subcortical brain networks that drive cognitive, social, and attentional functions that are often dysfunctional in psychiatric patients. These neurons are activated not only through Gs-coupled D1Rs and NMDA receptors, but also through Gq/ii-coupled M1 muscarinic acetylcholine receptors (M1Rs) that provoke calcium release from IP3-operated intracellular stores and also mediate endocannabinoid-dependent inhibition. However, there is a major gap in knowledge of the extent to which adolescent abuse of marijuana produces changes in the availability and functionality of these receptors in PFC neurons, which culminate in cognitive or social dysfunctions in adulthood. The proposed studies will test the Central Hypothesis that adult behavioral dysfunctions resulting from chronic adolescent administration of Δ9-THC are maintained by persistent suppression of NMDA/D1R and M1R/IP3 receptor systems that mediate the influx and intracellular release of calcium in dopamine-regulated prefrontal cortical neurons. The research will be conducted in male and female C57BL/6J mice that are available in wild-type and mutant forms that can be used for determining potentially critical sex-specific differences in the deleterious effects of adolescent marijuana, which are not directly assessable in humans. The first two Specific Aims will assess the potentially deleterious impact of chronic adolescent administration of Δ9-THC on the functional expression of ionotropic (NMDA) glutamate receptors and muscarinic (M1) acetylcholine receptors in D1R-containing output neurons within the adult PFC. Specific Aim 3 will assess the functional relevance of observed THC-induced changes in these receptor systems by examining whether they are accompanied by (1) depression of intracellular Ca2+ and (2) behavioral dysfunctions recapitulated by genetic or pharmacological disruption of NMDA/D1 or M1R/IP3 signaling in the prefrontal cortex. Together, this research will identify molecular targets useful for treating and/or preventing the adverse neurobehavioral abnormalities resulting from marijuana abuse during adolescence.

当今青少年娱乐性使用大麻的增加是一个主要的健康问题，因为 青春期滥用大麻的人患精神疾病的风险增加。这 精神症状包括认知功能异常，这主要是通过 前额皮质（PFC）和相关的边缘脑区域。 PFC 中的锥体细胞和中间神经元 表达由内源性大麻素和 Δ9-四氢- 激活的大麻素-1 受体 (CB1R) 大麻酚 (Δ9-THC)，大麻中主要的精神活性化合物。这些受体的慢性激活 Δ9-THC 下调内源性大麻素系统，该系统是经验依赖学习的关键调节因子 青春期的 PFC 尚未成熟。这种学习是由谷氨酸能钙流入所触发的 NMDA 受体由物理上和功能上与多巴胺 D1 样偶联的亚基组成 受体（D1R）。表达 D1R 的锥体细胞是 PFC 神经元中与控制最相关的神经元之一。 皮层下大脑网络驱动认知、社交和注意力功能，但这些功能在 精神病患者。这些神经元不仅通过 Gs 耦合的 D1R 和 NMDA 受体激活， 还通过 Gq/ii 偶联的 M1 毒蕈碱乙酰胆碱受体 (M1R) 激发钙释放 来自 IP3 操作的细胞内储存，还介导内源性大麻素依赖性抑制。然而， 对于青少年吸食大麻在多大程度上造成的变化，人们的认识存在重大差距。 PFC 神经元中这些受体的可用性和功能，最终导致认知或社交 成年后的功能障碍。拟议的研究将检验成人行为的中心假设 青少年长期服用 Δ9-THC 导致的功能障碍通过持续的维持 抑制介导细胞内流入和细胞内释放的 NMDA/D1R 和 M1R/IP3 受体系统 多巴胺调节的前额皮质神经元中的钙。该研究将在男性和女性中进行 C57BL/6J 小鼠有野生型和突变型，可用于确定潜在的 青少年大麻的有害影响存在关键的性别差异，这并不直接 可在人类中评估。前两个具体目标将评估慢性病的潜在有害影响 青少年服用 Δ9-THC 对离子型 (NMDA) 谷氨酸受体功能表达的影响 成人 PFC 内含有 D1R 的输出神经元中的毒蕈碱 (M1) 乙酰胆碱受体。具体的 目标 3 将通过以下方式评估观察到的 THC 诱导的这些受体系统变化的功能相关性： 检查它们是否伴有 (1) 细胞内 Ca2+ 抑制和 (2) 行为 由 NMDA/D1 或 M1R/IP3 信号传导的遗传或药理学破坏重现的功能障碍 前额皮质。总之，这项研究将确定可用于治疗和/或预防的分子靶点 青春期吸食大麻导致的不良神经行为异常。