Marijuana & Cytokine Actions on Rat Brain Mitogenesis

描述(由申请人提供)： 慢性药物滥用的一个常见结果是认知丧失或功能障碍。在许多这样的病例中，没有明确的神经病理学与这些缺陷相关。大麻类药物大麻就是一个很好的例子，在急性和慢性中毒后，大麻的使用最常与记忆力丧失有关。然而，没有任何与使用它相关的坦率神经病理学的确凿证据(参见。毒品“摇头丸”(3，4-MDMA)。 最近的证据表明，哺乳动物的大脑(包括人类)在成年后会继续产生新的神经元。此外，这一过程已被证明在新的学习和记忆中很重要。这项申请提出了一项研究，旨在研究β-四氢大麻酚(THC)对成年大鼠齿状回(DG)有丝分裂(细胞增殖)的影响，这是神经发生的第一阶段。这些影响也将在它们与促炎细胞因子IL-1β(IL-1β)相互作用的背景下进行研究，IL-1β在各种感染和应激条件下释放。 THC将以急性和慢性三种剂量通过腹膜腔给药。此外，这些动物中的一些还将长期给予IL-1β。在这些不同的药物治疗(或对照治疗)之后，所有动物都将被注射溴脱氧尿苷(BrdU)，并在两小时后处死。这些动物将被灌流，它们的大脑将被取出，并进行BrdU免疫反应。DG颗粒细胞层和门区的BrdU标记细胞将用光学显微镜进行定量。 据推测，慢性和急性的THC将抑制DG的有丝分裂，与应激相关的细胞因子IL-1β也将具有这种作用。进一步推测，这两种化合物在抑制DG有丝分裂方面的作用至少是相加的。

DESCRIPTION (provided by applicant): A common result of chronic drug abuse is cognitive loss or dysfunction. In many of these cases no definitive neuropathology is associated with these deficits. A case in point is the cannabinoid drug, marijuana, whose use is most often associated with memory loss, following both acute and chronic intoxication. There is not, however, any definitive evidence of frank neuropathology associated with its use (cf. the drug "ecstasy" 3,4-MDMA). Recent evidence indicates that the mammalian brain (including humans) continues to produce new neurons into adulthood. Additionally, this process has been shown to be important in new learning and memory. This application proposes research which examines the effects of the delta-tetrahydrocannabinol (THC) on mitogenesis (cell proliferation), the first phase of neurogenesis, in the dentate gyrus (DG) of adult rats. These effects will also be studied in the context of their interaction with the proinflammatory cytokine interleukin-1beta (IL-1beta), which is released under a variety of infectious and stressful conditions. THC will be administered intraperitoneally both acutely and chronically in three doses. In addition, some of these animals will also be given IL-1beta chronically. Following these various drug treatments (or control treatments), all animals will be administered bromodeoxyuridine (BrdU) and sacrificed two hours later. The animals will be perfused and their brains removed and processed for BrdU-immunoreactivity. BrdU-labeled cells in the granule cell layer and hilus of the DG will be quantified using light microscopy. It is hypothesized that chronic, and possibly acute, THC will suppress DG mitogenesis and that the stress-related cytokine IL- 1beta will also have this effect. It is further hypothesized that the actions of the two compounds will be at least additive in suppressing DG mitogenesis.