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

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 增加了患精神疾病的风险，是一个主要的公共卫生问题。例如，增加了 在大量使用青少年大麻的情况下，人们观察到精神病和精神病发病较早。 早期吸食大麻、精神障碍的发病年龄和 “纯”大麻使用者的首次住院治疗。然而，其背后的病理生理机制 早期使用大麻的不良影响，如扰乱社交、精神病和成瘾风险 仍有待阐明。更好地了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。 青春期是神经发育成熟的时期，特别是在中皮质-边缘系统。 (MCS)，一组相互关联的结构，涉及更高的认知功能、情绪、奖励和 社会行为。男性和女性的MCS发育速度不同。在青春期，社交 游戏是一种以MCS为基础的行为，它引导着社会互动的产生和适当的成熟。颠覆 青少年的社交游戏对成年人的行为有负面影响。受损的青少年社交游戏也可能是 这是新出现的精神病态的征兆。大麻的主要精神活性成分(即THC)与 丰富的CB1大麻素受体(CB1R)，与内源性大麻素竞争。CB1R是核心 内源性大麻素系统(ECS)的组成部分。ECS在整个MCS中都很丰富， 调节许多神经发育、神经元和突触过程，包括青少年的社交游戏。 我们实验室的最新发现支持了这样一个概念，即ECS功能障碍在多种疾病中起着关键作用 由环境或基因引起的神经精神疾病。 受到新的、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来研究 建立MCS中特定性别的ECS成分的发育和分布，以及这些因素如何影响 青少年大麻(THC)暴露的分子、突触和行为后果。我们的三个目标将： 1/描述和比较正常的神经元和突触反应的功能发育 雄性和雌性大鼠从青春期前到成年期的MCS。 2/建立ECS关键成分的表达和定位的发育模式 在大鼠的MCS中，以性别和年龄特定的方式。 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，这些研究的结果将定义新的结构、分子和功能突触底物 青少年吸食大麻对ECS功能和行为的性别影响。

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.