Behavioral Pharmacology of Synthetic Cannabinoids

其他项目信息-第7节-项目摘要/摘要 1滥用特制大麻素的情况增加，如JWH-018和AB-PINACA(以“香料”或“K2”的名称出售)， 2仍然是一个严重的公共卫生问题，尽管DEA对这些化合物进行了I级调度。 然而，对这些化合物的临床前研究一再证明它们是类似THC的。 出现4次呕吐、幻觉、癫痫发作，甚至死亡--这些影响以前与THC无关 5或其他大麻产品--表明合成大麻和植物大麻之间存在严重差异 6种大麻素。我们建议系统地表征不同化合物之间的药理差异。 7种大麻素(SCB)，基于它们在产生CB1受体介导的效应中的内在活性以及 8它们调节非大麻素效应的能力。该计划的首要目标是确定 9预测其滥用相关影响的药物之间的差异，并利用这些差异来识别 10项有用的战略，用于紧急管理仿制大麻类药物的有害影响。这些目标将 11通过解决三个假设来实现：1)SCB在CB1受体上的有效性不同；2)SCB具有 12其他神经递质系统的调节作用；以及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，我们建议使用一个独特的CB1 14拮抗剂AM6538，暂时灭活一部分CB1受体，然后评估一系列 15%的SCB产生抗伤害效应或扰乱正在进行的行为。剩余的受体比例 16 AM6538治疗后的每种激动剂将直接随SCBS的内在活性而变化，提供 17体内差异的量化测量(表观τ值)这些研究的第二个目的是基于 18前提是SCB的致幻作用与其他已知化合物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建立符合以下条件的检测方法 21可以确定SCB具有与其他迷幻剂类似的主观影响的程度。完整的 22或部分取代不同训练药物的短链苯系物的情况预计取决于 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在非人灵长类动物中SCBS的神经认知效应和强化效应 25在滥用倾向、致幻剂样特征和 26设计的大麻类药物的内在活性。这些研究的直接影响将是澄清 27 CB1疗效与SCB产品有害主观效应的关系。这将有助于 28描述新药在“灰色市场”出现时的特征，并通过以下方式开始确定机制 29这些短链苯系物的影响不同于植物大麻类物质。

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.