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: 10194433
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194433
• 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.

今天的青少年在娱乐使用大麻时升级是一个主要的健康问题，因为 在青少年期间滥用大麻的个体中精神疾病的风险增加。这 精神病症状包括认知功能的异常，这些功能主要通过 前额叶皮层（PFC）和相关的边缘大脑区域。 PFC中的锥体细胞和中间神经元 表达大麻素-1受体（CB1RS）被内源性大麻素激活，并被Δ9-四氢 大麻的主要精神活性化合物大麻醇（δ9-THC）。通过 Δ9-THC下调了内源性大麻素系统，该系统是经验依赖性学习的关键调节剂 在青少年的静止PFC中。通过谷氨酸能的钙影响触发了这种学习 NMDA受体由物理和功能偶联到多巴胺D1样的亚基组成 受体（D1R）。表达D1RS的锥体细胞是最涉及控制的PFC神经元之一 驱动认知，社交和注意力功能的皮质下脑网络通常在 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 而且还通过GQ/II偶联的M1毒蕈碱乙酰胆碱受体（M1R），引起钙释放 来自IP3稳定的细胞内存储，还介导内源性大麻素依赖性抑制作用。然而， 知道青少年滥用大麻会产生变化的程度，存在一个重大差距 这些受体在PFC神经元中的可用性和功能，这些受体在认知或社会上达到顶峰 成年期功能障碍。拟议的研究将检验成人行为的中心假设 慢性青少年给药δ9-THC引起的功能障碍是通过持续的 NMDA/D1R和M1R/IP3受体系统的抑制，介导了介导的影响和细胞内释放 多巴胺调节的前额叶皮质神经元中的钙。该研究将在男性和女性中进行 C57BL/6J小鼠以野生型和突变体形式可用，可用于确定潜在的 青少年大麻的有害影响的批判性别特定差异，这不是直接的 可以在人类中评估。前两个具体目标将评估慢性的潜在删除影响 青少年在离子型（NMDA）谷氨酸受体的功能表达上施用Δ9-THC 成年PFC中含D1R的输出神经元中的毒蕈碱（M1）乙酰胆碱受体。具体的 AIM 3将评估观察到的THC诱导的受体系统变化的功能相关性 检查它们是否伴随着（1）细胞内Ca2+和（2）行为的抑郁症 NMDA/D1或M1R/IP3信号在概括性或药物破坏中概括的功能障碍 前额叶皮层。这项研究将确定可用于治疗和/或预防的分子靶标 青少年期间大麻滥用导致的不良神经行为异常。

项目成果

Prefrontal cortical distribution of muscarinic M2 and cannabinoid-1 (CB1) receptors in adult male mice with or without chronic adolescent exposure to Δ9-tetrahydrocannabinol.

成年雄性小鼠中毒蕈碱 M2 和大麻素 1 (CB1) 受体的前额皮质分布，有或没有慢性青少年暴露于 α9-四氢大麻酚。

• DOI: 10.1093/cercor/bhac024
• 发表时间: 2022
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Garzón,Miguel;Chan,June;Mackie,Ken;Pickel,VirginiaM
• 通讯作者: Pickel,VirginiaM

Chronic adolescent exposure to ∆9-tetrahydrocannabinol decreases NMDA current and extrasynaptic plasmalemmal density of NMDA GluN1 subunits in the prelimbic cortex of adult male mice.

青少年长期接触α9-四氢大麻酚会降低成年雄性小鼠前边缘皮质中的NMDA电流和NMDA GluN1亚基的突触外质膜密度。

• DOI: 10.1038/s41386-019-0466-9
• 发表时间: 2020
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Pickel,VirginiaM;Bourie,Faye;Chan,June;Mackie,Ken;Lane,DianeA;Wang,Gang
• 通讯作者: Wang,Gang