Neurobehavioral Effects of Combined MDMA (Ecstasy) and THC Exposure During Adoles

描述(申请人提供)：使用3，4-亚甲基二氧基甲基苯丙胺(MDMA，或“摇头丸”)在美国是一个严重的健康问题。大剂量的MDMA损害成年动物的5-羟色胺能系统，类似的后果可能发生在大量服用摇头丸的人身上。许多研究还发现摇头丸的使用与认知缺陷、高度焦虑和冲动增加之间存在关联。然而，大多数摇头丸重度使用者也经常使用大麻，这一事实混淆了对这些结果的解释，从而提出了关于摇头丸/大麻共同使用者中观察到的认知和神经精神异常的来源的重要问题。由于摇头丸的使用通常始于青春期，并且通常间歇性地发生(例如，在周末的舞会上)，我们的实验室开发了一种间歇性接触青少年MDMA的新型大鼠模型。使用这一模型治疗的动物显示出相对温和的5-羟色胺能神经毒性(与高剂量暴饮法相比)，这与摇头丸使用者5-羟色胺能系统的神经成像研究结果相似。在随后的行为测试中，服用MDMA的动物表现出记忆障碍以及其他可能表明冲动增加的影响。这项拟议的研究是一个试验性项目，旨在调查重复给予青春期雄性和雌性大鼠MDMA和9-四氢大麻酚(THC；大麻中的主要精神活性成分)对行为和神经毒性的单独和联合影响。从给药期结束后的一周开始，我们将测试药物治疗和对照动物在几个空间和非空间学习和记忆测试中的表现，或者他们在几个焦虑或冲动测试中的行为和肾上腺皮质反应。将确定这些治疗对局部脑5-羟色胺转运体表达的影响，以确定行为和激素反应与涉及学习、记忆和焦虑的关键大脑区域的5-羟色胺能神经毒性之间的可能关系。这些研究将提供关于MDMA和THC在青春期暴露的单独和联合影响的重要新信息，从而有助于解决一个持续困扰临床摇头丸文献的有争议的问题。与公众健康相关：许多年轻人经常服用摇头丸，有科学证据表明，这种使用对吸毒者的大脑功能和行为有不利影响。由于大多数摇头丸使用者也吸食大麻，研究人员很难确定摇头丸的一些负面后果，特别是那些涉及记忆缺陷的负面后果，是否可能与反复接触大麻有关。这项拟议的研究将通过对实验动物进行对照研究来确定这两种药物单独或联合使用对学习、记忆和焦虑的影响，从而帮助回答这一重要问题。

DESCRIPTION (provided by applicant): Use of 3,4-methylenedioxymethamphetamine (MDMA, or "Ecstasy") is a significant health problem in the United States. High doses of MDMA damage the serotonergic system in adult animals, and similar consequences may occur in heavy Ecstasy users. Many studies have also found an association between Ecstasy use and cognitive deficits, heightened anxiety, and increased impulsivity. However, interpretation of these findings is confounded by the fact that most heavy Ecstasy users also regularly use cannabis, thus raising important questions as to the source of the cognitive and neuropsychiatric abnormalities observed in Ecstasy/cannabis co-users. Because Ecstasy use typically begins during adolescence and commonly occurs intermittently (e.g., on weekends at dances), our laboratory has developed a novel rat model of intermittent adolescent MDMA exposure. Animals treated using this model show a relatively modest serotonergic neurotoxicity (compared to high-dose binge regimens) that resembles the results obtained from neuroimaging studies of the serotonergic system in Ecstasy users. In subsequent behavioral testing, the MDMA-treated animals showed memory impairment as well as other effects that may be indicative of increased impulsivity. The proposed studies represent a pilot project designed to investigate the separate and combined behavioral and neurotoxic effects of MDMA and ?9-tetrahydrocannabinol (THC; the main psychoactive ingredient in cannabis) given repeatedly to adolescent male and female rats. Beginning at 1 week following the end of the dosing period, we will test drug-treated and control animals for their performance in several tests of spatial and non-spatial learning and memory, or for their behavioral and adrenocortical responses in several tests of anxiety or impulsivity. The effects of the treatments on regional brain serotonin transporter expression will be ascertained to determine possible relationships between behavioral and hormonal responses and serotonergic neurotoxicity in key brain areas involved in learning, memory, and anxiety. These studies will provide important new information on the separate and combined effects of MDMA and THC exposure during adolescence, thereby helping to resolve a controversial issue that has continued to plague the clinical Ecstasy literature. PUBLIC HEALTH RELEVANCE: Many young people regularly use the drug "Ecstasy", and there is scientific evidence that such use has adverse effects on the users' brain function and behavior. Because most Ecstasy users also smoke marijuana, researchers have had difficulty determining whether some of the negative consequences of Ecstasy, especially those involving memory deficits, might instead be related to repeated marijuana exposure. The proposed research will help answer this important problem by using controlled studies of experimental animals to determine the influence of these two drugs separately or together on learning, memory, and anxiety.