Behavioral Pharmacology of Synthetic Cannabinoids

合成大麻素的行为药理学

• 批准号: 10424489
• 负责人: CAROL A PARONIS
• 金额: $ 52.5万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424489
• 关键词: Acute; Address; Adverse effects; Agonist; Awareness; Behavior; Behavioral; Biological Assay; CNR1 gene; Cannabinoids; Cannabis; Cessation of life; Characteristics; Chemical Structure; Cognitive; Coma; Data; Emergency Situation; Excitatory Amino Acid Antagonists; Funding; Furosemide; Glutamate Receptor; Glutamates; Goals; Hallucinations; Hallucinogens; Indazoles; Indoles; K2/Spice; Ketamine; Learning; Legal; Manufacturer Name; Measures; Mediating; Medical; Methods; Modeling; Modification; Monkeys; Neurocognitive; Neurotransmitters; Opioid agonist; Pharmaceutical Preparations; Pharmacology; Physiological; Plants; Procedures; Psychoses; Public Health; Rattus; Renal function; Reporting; Research; Rodent; Schedule; Seizures; Self Administration; Short-Term Memory; Spices; Stimulus; Stress Tests; System; Tetrahydrocannabinol; Toxic effect; Training; Ursidae Family; Vomiting; abuse liability; antagonist; base; behavioral pharmacology; cannabinoid drug; combat; drug discrimination; endogenous opioids; experimental study; flexibility; hazard; improved; in vivo; kappa opioid receptors; monoamine; neurotransmission; non-cannabinoid; nonhuman primate; novel; novel therapeutics; preclinical study; presynaptic; programs; receptor; salvinorin A; synthetic cannabinoid; tau Proteins; tool; touchscreen

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.

其他项目信息 - 第 7 节 - 项目摘要/摘要 1 设计大麻素的滥用增加，例如 JWH-018 和 AB-PINACA（以“Spice”或“K2”出售）， 尽管 DEA 将这些化合物列为 I 类，但 2 仍然是一个严重的公共卫生问题。 3 这些化合物的临床前研究多次发现它们与 THC 类似，但是 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 - 表明合成大麻和植物衍生大麻之间存在严重差异 6 种大麻素。我们建议系统地表征合成药物之间的药理学差异 7 种大麻素 (SCB) 基于其产生 CB1 受体介导作用的内在活性以及 8 它们调节非大麻素效应的能力。该计划的总体目标是确定 药物之间的 9 种差异可预测其滥用相关效应并利用这些差异来识别 急性管理设计大麻素有害影响的 10 种有用策略。这些目标将 11 通过解决三个假设来实现：1）SCB 对 CB1 受体的功效各不相同； 2) SCB 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 反映在它们的有害和强化作用上。为了实现这些目标，我们建议使用独特的 CB1 14 拮抗剂 AM6538，暂时灭活部分 CB1 受体，然后评估一系列能力 15 种 SCB 可产生抗伤害作用或扰乱正在进行的行为。剩余的受体分数 16 AM6538 治疗后的每种激动剂将直接随 SCB 的内在活性变化，从而提供 17 体内差异的可量化测量（表观 τ 值） 这些研究的第二个目标是基于 18 前提是 SCB 的致幻作用与其他已知物质的作用有一些相似之处。 19 种致幻剂，即 LSD、salvinorin A 或氯胺酮，分别由 5-HT2、κ-阿片类药物或氯胺酮介导 20个谷氨酸受体。为了实现这一目标，将使用药物区分程序来建立能够 21 可以确定 SCB 具有与其他致幻剂类似的主观效果的程度。完整的 22 不同训练药物的 SCB 或部分替代概况预计将取决于 23 SCB 的化学结构或其内在活性。 Lastly, we propose experiments to evaluate the 24 SCB 对非人类灵长类动物的神经认知效应和强化效应，以确定或阐明 25 滥用倾向、致幻性特征和致幻剂之间存在的药理学关系 26 设计大麻素药物的内在活性。这些研究的直接影响将是阐明 27 CB1功效与SCB产品有害主观影响之间的关系。这将有助于 28 描述“灰色市场”中出现的新药的特征，并开始通过以下方式确定机制： 29 这些 SCB 的作用与植物大麻素的作用不同。