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 在青少年时期滥用大麻的人患精神疾病的风险增加。的 精神病症状包括认知功能异常，其主要通过 前额叶皮层（PFC）和相关的边缘脑区域。前额叶皮层的锥体细胞和中间神经元 表达大麻素-1受体（CB 1 R），由内源性大麻素和Δ9-四氢- 大麻酚（Δ9-THC），大麻中主要的精神活性化合物。这些受体的慢性激活， Δ9-THC下调内源性大麻素系统，这是经验依赖性学习的关键调节因子 在青春期尚未成熟的前额叶皮层这种学习是由钙离子通过海马神经元流入触发的。 NMDA受体由在物理和功能上与多巴胺D1样 受体（D1 Rs）。表达D1 R的锥体细胞是PFC神经元中最参与控制D1 R的神经元。 皮质下大脑网络驱动认知，社交和注意力功能，这些功能在 精神病患者。这些神经元不仅通过Gs-coupled D1 Rs和NMDA受体被激活， 而且还通过Gq/ii偶联的M1毒蕈碱乙酰胆碱受体（M1 Rs）引起钙释放 从IP 3操作的细胞内商店，也介导内源性大麻素依赖性抑制。然而，在这方面， 青少年滥用大麻在多大程度上改变了 这些受体在PFC神经元中的可用性和功能性，最终导致认知或社交 成年期的功能障碍。拟议中的研究将检验中心假设，即成年人的行为 由长期青少年施用Δ9-THC引起的功能障碍由持续的 抑制NMDA/D1 R和M1 R/IP 3受体系统，其介导 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 C57 BL/6 J小鼠，其以野生型和突变体形式可用，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 在人类中可评估。前两个具体目标将评估慢性疾病的潜在有害影响。 青少年给予Δ9-THC对离子型（NMDA）谷氨酸受体功能表达的影响 和毒蕈碱（M1）乙酰胆碱受体在D1 R的输出神经元内的成人PFC。 目的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： 检查它们是否伴随（1）细胞内Ca 2+的抑制和（2）行为学改变。 通过NMDA/D1或M1 R/IP 3信号传导的遗传或药理学破坏再现的功能障碍， 前额皮质总之，这项研究将确定用于治疗和/或预防的分子靶点。 青少年时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.