Behavioral Pharmacology of Synthetic Cannabinoids

其他项目信息-第7节-项目概要/摘要 1滥用设计师大麻素的增加，如JWH-018和AB-PINACA（以“Spice”或“K2”出售）， 2继续是一个严重的公共卫生问题，尽管一类调度这些化合物的DEA。 3这些化合物的临床前研究已经反复鉴定它们是THC样的，然而， 4次出现呕吐、幻觉、癫痫发作，甚至死亡-以前与THC无关的影响 5或其他大麻产品-表明合成和植物衍生的大麻产品之间存在严重差异 6 cannabinoids.我们建议系统地描述合成药物之间的药理学差异， 7大麻素（SCB）基于其产生CB 1受体介导的作用的内在活性，以及 8他们调节非大麻素作用的能力。该计划的首要目标是确定 9药物之间的差异，预测其滥用相关的影响，并使用这些差异，以确定 10有用的策略急性管理的设计师大麻素的有害影响。这些目标将 11可以通过解决三个假设来实现：1）SCB对CB 1受体的功效不同; 2）SCB具有 12对其他神经递质系统的调节作用; 3）SCB内在活性的差异是 13反映在其有害和强化的影响。为了实现这些目标，我们建议使用一个独特的CB 1 14拮抗剂，AM 6538，暂时阻断一部分CB 1受体，然后评估一系列 15 SCBs产生抗伤害效应或破坏正在进行的行为。剩余的受体分数 AM 6538处理后的每种激动剂将直接随SCB的内在活性而变化， 这些研究的第二个目的是基于它们在体内的差异的17个可量化的测量（表观τ值）。 18的前提是SCB的致幻作用与其他已知的致幻作用有一些相似之处。 19种致幻剂，即LSD、鼠尾草素A或氯胺酮，它们分别由5-HT 2、κ-阿片样物质或 20个谷氨酸受体。为了实现这一目标，将使用药物鉴别程序来建立测定， 21可以确定SCB与其他致幻剂相似的主观效果的程度。充分 预期SCB对不同训练药物的替代或部分替代概况取决于训练药物的剂量。 23 SCB的化学结构或其内在活性。最后，我们提出了实验来评估 24 SCB在非人灵长类动物中的神经认知效应和强化效应，以确定或阐明 25滥用倾向、致幻样特征和 26设计师大麻素药物的内在活性。这些研究的直接影响将是阐明 27 CB 1功效与SCB产品的有害主观效应之间的关系。这将有助于 28.对出现在“灰色市场”的新型药物进行定性，并开始通过以下方式确定机制： 这些SCB的作用不同于植物大麻素的作用。

OTHER PROJECT INFORMATION - SECTION 7 - PROJECT SUMMARY/ABSTRACT 1 Increased abuse of designer cannabinoids, such as JWH-018 and AB-PINACA (sold as “Spice” or “K2”), 2 continues to be a severe public health concern despite Class I scheduling of these compounds by the DEA. 3 Preclinical studies of these compounds have repeatedly identified them as being THC-like, however 4 occurrences of emesis, hallucinations, seizures, and even death - effects not previously associated with THC 5 or other cannabis products - indicates that there are grave differences between synthetic and plant-derived 6 cannabinoids. We propose to systematically characterize the pharmacological differences among synthetic 7 cannabinoids (SCBs) based on their intrinsic activity in producing CB1 receptor-mediated effects as well as 8 their ability to modulate noncannabinoid effects. The overarching goals of this program are to determine 9 differences between drugs that predict their abuse-related effects and to use these differences to identify 10 useful strategies for acute management of the deleterious effects of designer cannabinoids. These goals will 11 be achieved by addressing three hypotheses: 1) SCBs vary in efficacy at CB1 receptors; 2) SCBs have 12 modulatory effects at other neurotransmitter systems; and 3) differences in the intrinsic activity of SCBs is 13 reflected in their deleterious and reinforcing effects. To address these aims, we propose to use a unique CB1 14 antagonist, AM6538, to temporarily inactivate a portion of CB1 receptors and then assess the ability of a range 15 of SCBs to produce antinociceptive effects or disrupt ongoing behavior. The fraction of receptors remaining for 16 each agonist following AM6538 treatment will vary directly with the intrinsic activity of the SCBs, providing a 17 quantifiable measure of their differences in vivo (apparent τ-value) The second aim of these studies is based 18 on the premise that the hallucinogenic effects of SCBs bear some similarities to the effects of other known 19 hallucinogens, namely LSD, salvinorin A, or ketamine, which are mediated by, respectively, 5-HT2, κ-opioid, or 20 glutamate receptors. To address this aim, drug discrimination procedures will be used to establish assays that 21 can determine the extent to which SCBs have subjective effects similar to those of other hallucinogens. The full 22 or partial substitution profile of the SCBs for the different training drugs is expected to be dependent on the 23 chemical structure of the SCBs or on their intrinsic activity. Lastly, we propose experiments to evaluate the 24 neurocognitive effects and reinforcing effects of SCBs in nonhuman primates in order to identify or clarify the 25 pharmacological relationship that exists between the abuse liability, the hallucinogenic-like profile, and the 26 intrinsic activity of designer cannabinoid drugs. The direct impact of these studies will be to elucidate the 27 relationship between CB1 efficacy and deleterious subjective effects of SCB products. This will aid in 28 characterizing novel drugs as they emerge in the `grey market', and, as well, begin to identify mechanisms by 29 which the effects of these SCBs differ from those of phytocannabiniods.