Sex-specific critical periods determine the effects of cannabinoids on the mesocorticolimbic system

性别特异性关键期决定大麻素对中皮质边缘系统的影响

• 批准号: 9402779
• 负责人: OLIVIER JJ MANZONI
• 金额: $ 31.14万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402779
• 关键词: Adolescence; Adolescent; Adolescent and Young Adult; Adult; Adverse effects; Affect; Age; Amygdaloid structure; Anatomy; Automobile Driving; Behavior; Behavioral; Biochemical; Biological; Brain; CNR1 gene; Cannabinoids; Cannabis; Chronic; Cognition; Cognitive; Consumption; Data; Development; Emotions; Endocannabinoids; Exposure to; Female; Functional disorder; Genetic; Hippocampus (Brain); Hospitalization; Impairment; Laboratories; Life; Limbic System; Mediating; Mental disorders; Methods; Modeling; Molecular; Morphology; Neurons; Nucleus Accumbens; Outcome Study; Pattern; Physiology; Plants; Play; Portraits; Predisposition; Prefrontal Cortex; Preparation; Prevention program; Process; Property; Psychopathology; Psychotic Disorders; Public Health; Public Policy; Publishing; Rattus; Reagent; Rewards; Risk; Rodent Model; Role; Sex Characteristics; Social Behavior; Social Interaction; Stress; Structure; Synapses; Synaptic plasticity; System; Systems Development; THC exposure; Tetrahydrocannabinol; Treatment Protocols; Validation; Ventral Tegmental Area; Work; addiction; age related; base; cognitive function; critical developmental period; critical period; design; early onset; endogenous cannabinoid system; endophenotype; exhaustion; experimental study; illicit drug use; interdisciplinary approach; male; marijuana legalization; marijuana use; marijuana user; negative affect; neural circuit; neurodevelopment; neuron development; neuropsychiatric disorder; neuroregulation; postnatal; preadolescence; response; sex; social; synaptic function; therapy development

Cannabis is the most frequently used illicit drug. Its widespread use in adolescents is associated with an increased risk for mental illness and is a major public health concern. For example, an increased rate of psychosis and an earlier onset of psychotic illness have been observed with heavy adolescent cannabis use. There is also a correlation between early cannabis use, the age at onset of psychotic disorders and the age at first hospitalization for 'pure' cannabis users. However, the pathophysiological mechanisms underlying the adverse effects of early cannabis use, such as perturbed social interactions, psychosis and addiction risk remain to be elucidated. A better understanding of these mechanisms is necessary to develop therapies & effective prevention programs, and to inform decisions on public policy, including cannabis legalization. Adolescence is a period of profound neurodevelopmental maturation, notably in the mesocortico-limbic system (MCS), an ensemble of interconnected structures involved in higher cognitive functions, emotions, reward and social behaviors. MCS development occurs at different rates in males and females. During adolescence, social play, an MCS-based behavior, guides the emergence and proper maturation of social interactions. Disruption of social play in the adolescent negatively affects adult behaviors. Impaired adolescent social play may also be a sign of emerging psychopathology. The main psychoactive ingredient of cannabis (i.e., THC) engages the abundant CB1 cannabinoid receptor (CB1R), competing with endogenous cannabinoids. CB1Rs are a core component of the endogenous cannabinoid system (ECS). The ECS is abundant throughout the MCS and modulates many neurodevelopmental, neuronal and synaptic processes, including adolescent social play. Recent discoveries from our laboratories fueled the concept that ECS dysfunction plays a key role in diverse neuropsychiatric diseases of environmental or genetic origin. Motivated by new, unpublished data, and using a rodent model, we propose a multi-disciplinary approach to establish the sex-specific development and distribution of ECS components in the MCS and how these affect the molecular, synaptic and behavioral consequences of adolescent cannabis (THC) exposure. Our 3 aims will: 1/ Characterize and compare the normal functional development of neuronal and synaptic responses in the MCS between male and female rats from pre-adolescence to adulthood. 2/ Establish the developmental patterns of expression and localization of key components of the ECS in the rat MCS in a sex and age-specific fashion. 3/ Determine the sex-specific functional (molecular, synaptic, and behavioral) consequences of THC exposure during critical periods of adolescence and adulthood. Together, the results of these studies will define new structural, molecular and functional synaptic substrates of the sex-specific effects of adolescent cannabis use on ECS function and behavior.

大麻是使用最频繁的非法药物。它在青少年中的广泛使用与 精神疾病的风险增加，是一个主要的公共卫生问题。例如，增长率 在青少年大量使用大麻的情况下，观察到精神病和精神病的早期发作。 早期使用大麻、精神病发作时的年龄和精神病发作时的年龄之间也存在相关性。 第一次住院治疗的“纯”大麻用户。然而，潜在的病理生理机制， 早期使用大麻的不利影响，如扰乱社会交往、精神病和成瘾风险 仍有待阐明。更好地理解这些机制对于开发治疗方法是必要的， 有效的预防方案，并为公共政策决策提供信息，包括大麻合法化。 青春期是一个神经发育成熟的时期，尤其是中皮质-边缘系统 (MCS)，一个涉及高级认知功能，情感，奖励和 社会行为MCS在男性和女性中的发展速度不同。在青春期，社会 游戏是一种基于MCS的行为，它引导着社会互动的出现和适当的成熟。中断 青少年的社交游戏对成年人的行为有负面影响。青少年社交游戏受损也可能是 一种精神病态的征兆大麻的主要精神活性成分（即，THC）接合 丰富的CB 1大麻素受体（CB 1 R），与内源性大麻素竞争。CB 1 R是一个核心 内源性大麻素系统（ECS）。ECS在整个MCS中很丰富， 调节许多神经发育、神经元和突触过程，包括青少年的社会游戏。 我们实验室的最新发现推动了ECS功能障碍在多种疾病中起关键作用的概念。 环境或遗传源性神经精神疾病。 受新的未发表的数据的启发，并使用啮齿动物模型，我们提出了一种多学科的方法， 建立MCS中ECS组分的性别特异性发育和分布，以及这些组分如何影响 青少年大麻（THC）暴露的分子，突触和行为后果。我们的三个目标是： 1/表征和比较神经元和突触反应的正常功能发育， 雄性和雌性大鼠从青春期前到成年的MCS。 2/建立ECS关键组分的表达和定位的发育模式 以性别和年龄特异性的方式在大鼠MCS中。 3/确定THC的性别特异性功能（分子，突触和行为）后果 在青春期和成年期的关键时期暴露。 总之，这些研究的结果将确定新的结构，分子和功能突触基板的 青少年使用大麻对ECS功能和行为的性别特异性影响。