Cannabinoid Approaches for Treatment of Tourette's Syndrome

描述（由申请人提供）：精神抑制剂仍然是治疗抽动秽语综合征（TS）的主要方式。然而，这些药物具有严重的副作用，包括烦躁不安、认知缺陷和迟发性运动障碍。最近的随机双盲安慰剂对照临床试验表明，δ-9-四氢大麻酚（THC）减少TS的症状。这些发现证实了过去几十年来的许多轶事报道，表明大麻改善了TS的一些症状，并表明大麻素神经传递的激活是治疗TS的合理治疗策略。然而，由于与滥用有关的问题，用THC治疗TS不是一个可行的选择。直接激活大脑中大麻素受体的其他药理学方法也存在问题，因为CB 1受体，大脑中的主要大麻素受体，通过直接外源激动剂激活变得脱敏。靶向大麻素神经传递治疗TS的另一个可预见的问题是，这种疾病在青春期表现出来。在此期间接触大麻与长期不良认知影响和发展其他精神疾病的倾向增加有关。本提案的目的是探索一种替代方法的可行性，以增强大麻素神经传递治疗TS，这可能与上述缺点无关。该方法涉及通过降低内源性大麻素（eCB）和2-AG的水解或吸收速率来操纵它们的水平。几种脑渗透性化合物最近被描述为阻断eCB转运蛋白和花生四烯酸水解的有效药理学工具。我们建议（1）探索这些药物在逆转成年和青春期大鼠TS动物模型中的抽动样行为的有效性，（2）确定青春期早期大鼠重复暴露于这些化合物对青春期后期和成年大鼠认知和情感功能的影响。预计这些研究的结果，除了探索TS的新治疗方法的可行性外，还将为未来关于eCB在正常发育和疾病状态下调节运动和认知功能的作用的机制研究提供基础。与公共卫生的相关性：目前用于治疗抽动秽语综合征的药物效果最低或具有严重的副作用。这项临床前提案旨在完成探索性研究，以确定这种儿童神经精神障碍的新治疗选择的可行性和安全性。

DESCRIPTION (provided by applicant): Neuroleptics remain the primary mode of treatment for Tourette's syndrome (TS). However, these drugs have profound side effects including dysphoria, cognitive deficits, and tardive dyskinesia. Recent randomized double- blind placebo-controlled clinical trials have shown that delta-9-tetrahdrocannabinol (THC) reduces symptoms of TS. These findings substantiate numerous anecdotal reports in the last several decades indicating that cannabis ameliorates some symptoms of TS and suggest that activation of cannabinoid neurotransmission is a plausible treatment strategy for treatment of TS. Treatment of TS with THC, however, is not a feasible option because of abuse-related concerns. Other pharmacological approaches that directly activate cannabinoid receptors in the brain are also problematic because the CB1 receptor, the primary cannabinoid receptor in the brain, becomes desensitized by direct exogenous agonist activation. Another foreseeable problem with targeting cannabinoid neurotransmission for treatment of TS is that this disorder is manifested during adolescence. Exposure to cannabis during this period has been linked to long-term adverse cognitive effects and increased propensity to develop other psychiatric disorders. The aim of this proposal is to explore the feasibility of an alternative approach to enhance cannabinoid neurotransmission for treatment of TS which may not be associated with the aforementioned shortcomings. The approach involves manipulating levels of endogenous cannabinoids (eCB) anandemide and 2-AG by either reducing their hydrolysis or rate of uptake. Several brain permeable compounds have been recently described as effective pharmacological tools for blocking eCB transporter and anandamide hydrolysis. We propose to (1) explore the effectiveness of these agents in reversing tic-like behaviors in several animal models of TS in both adult and adolescent rats and, (2) determine the effect of repeated exposure to these compounds in early adolescent rats on cognitive and affective functioning in late adolescent and adult rats. It is anticipated that the results of these studies will, in addition to exploring the feasibly of a novel treatment approach for TS, provide the basis for future mechanistic studies on the role of eCB in regulating motor and cognitive functions during normal development and in disease states. Relevance to public health: Drugs used presently to treat Tourette's syndrome are minimally effective or have profound side effects. This preclinical proposal aims to complete exploratory studies to determine the feasibility and safety of a novel treatment option for this childhood neuropsychiatric disorder.