Aberrant prefrontal cortical plasticity and neurobehavioral consequences of adolescent marijuana

当今青少年娱乐性使用大麻的升级是一个主要的健康问题，因为 在青春期滥用大麻的人患精神障碍的风险增加。这个 精神症状包括认知功能的异常，这种异常主要是通过 前额叶皮质(PFC)和相关的边缘脑区。前额叶的锥体细胞和中间神经元 表达大麻素-1受体(CB1Rs)，该受体可被内源性大麻素和Δ-9-四氢大麻激活. 大麻酚(Δ9-THC)，大麻中的主要精神活性化合物。这些受体的慢性激活通过 Δ9-THC下调内源性大麻素系统，内源性大麻素系统是经验依赖学习的关键调节因子 在青春期仍不成熟的一等兵中。这种学习是由谷氨酸能钙离子内流触发的 NMDA受体由物理上和功能上与类多巴胺D1偶联的亚基组成 受体(D1Rs)。表达D1Rs的锥体细胞是与控制有关的PFC神经元之一 皮质下大脑网络驱动认知、社交和注意力功能，这些功能通常在 精神病患者。这些神经元不仅通过Gs偶联的D1Rs和NMDA受体激活， 也通过GQ/II偶联的M1乙酰胆碱受体(M1Rs)刺激钙释放 从IP3操作的细胞内储存，也介导内源性大麻素依赖的抑制。然而， 对于青少年滥用大麻在多大程度上会带来变化，人们的认识存在重大差距 这些受体在PFC神经元中的可用性和功能，最终导致认知或社交 成年期的功能障碍。拟议的研究将检验中心假设，即成年人的行为 青少年长期服用Δ-9-Thc所致的功能障碍可通过持久化维持 抑制NMDA/D1R和M1R/IP3受体系统介导的内流和胞内释放 多巴胺调节的前额叶皮质神经元中的钙。这项研究将在男性和女性中进行 C57BL/6J小鼠有野生型和突变型，可用于确定潜在的 青少年大麻有害影响的关键性别差异，这不是直接的 在人类身上可以评估。前两个具体目标将评估慢性疾病的潜在有害影响 青春期服用Δ-9-Thc对谷氨酸受体功能表达的影响 成年PFC内含D1R的输出神经元的M_1乙酰胆碱受体。特定的 AIM 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 检查是否伴有(1)细胞内钙离子的抑制和(2)行为 NMDA/D1或M1R/IP3信号的遗传或药物干扰导致的功能障碍 前额叶皮质。总之，这项研究将确定对治疗和/或预防有用的分子靶点。 青春期滥用大麻导致的不良神经行为异常。

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.