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.

如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

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