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

基本信息

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
项目类别：
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

项目摘要

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。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）是大麻中主要的精神活性化合物，通过慢性激活这些受体。 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在青春期尚未成熟的 PFC 中，这种学习是由谷氨酸能的钙流入触发的。 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 的锥体细胞是与控制最相关的 PFC 神经元之一。皮层下大脑网络驱动认知、社交和注意力功能，但这些功能在这些神经元不仅通过 Gs 偶联的 D1R 和 NMDA 受体被激活，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 操作的细胞内储存并介导内源性大麻素依赖性抑制。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，可用于潜在的确定青少年大麻的有害影响存在关键的性别差异，这并不直接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。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这项研究将共同确定可用于治疗和/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。