Molecular sites of delta-9-THC and synthetic cannabinoid actions on brain function

在我们正在进行的研究中，以确定大麻素改变大脑功能的机制，我们一直在与NIDA内部研究计划的设计药物研究单位（DDRU）合作，比较“设计”大麻素与传统“天然”大麻素的药理作用，如在大麻植物中发现的δ -9-四氢大麻酚（δ -9- thc）。设计大麻素是一种精神活性分子，通常以“香”、“香料”或其他与植物相关的配方销售。这些药物的精神活性成分通常是由业余化学家在秘密实验室合成的，在大多数情况下，它们的结构类似于大麻素分子。合成大麻素是批量生产并喷洒在植物材料上的。这些分子是在没有监管控制的非法实验室制造的，这一事实经常导致接触掺假和污染物，从而导致意想不到的毒性。此外，这些合成大麻素的结构使得它们对δ -9- thc激活的相同大麻素受体具有更强的作用和更长的作用持续时间。虽然这些药物中有许多被广泛使用，但它们的安全性通常未经测试，其完整的药理作用位点仍然未知。这些化合物的非法性质及其不完全了解的药理作用导致世界范围内使用这些药物的个人急诊室就诊人数大幅增加。

In our ongoing studies to identify the mechanisms through which cannabinoids alter brain function, we have been collaborating with the Designer Drug Research Unit (DDRU) at the NIDA Intramural Research Program, to compare the pharmacological effects of "designer" cannabinoids with those of conventional "natural" cannabinoids such at delta-9-tetrahydrocannabinol (delta-9-THC), found in the marijuana plant. Designer cannabinoids are psychoactive molecules that are often marketed as "incense", "spice" or other plant-related formulations. The psychoactive components of these drugs are typically synthesized in clandestine laboratories by amateur chemists, and in most cases structurally resemble cannabinoid molecules. The synthetic cannabinoids are made in bulk and sprayed onto plant material. The fact that these molecules are made in illicit laboratories without regulatory control often leads to exposure to adulterants and contaminants that can result in unintended toxicity. In addition, the structure of these synthetic cannabinoids is such that they have stronger effects, and longer durations of action at the same cannabinoid receptors that are activated by delta-9-THC. Although many of these drugs are widely consumed, their safety is generally untested, and their complete pharmacological sites of action remain unknown. The illicit nature of these compounds and their incompletely understood pharmacological actions has resulted in a large increase in world-wide emergency room visits by individuals using these drugs. Our initial studies have examined 3 compounds that were isolated from material seized by the U.S. Drug Enforcement Agency (DEA), and subsequently synthesized by professional chemists. These studies show that the compounds AM-2201, and XLR-11 are full agonists at CB1 receptors that inhibit glutamate release in the hippocampus. This is in contrast to delta-9-THC, which purportedly acts as a partial agonist, demonstrating approximately one-half of the ability to inhibit glutamate responses as the synthetic molecules. In addition, these synthetic cannabinoids were much more potent than delta-9-THC on this measure. Another compound that we tested, known as JWH-018, was also more efficacious than delta-9-THC, but less potent than the other 2 synthetic compounds. Our general conclusion thus far is that the synthetic cannabinoids can bind to the cannabinoid CB1 receptor with much greater potency and efficacy than delta-9-THC. We predict that this will lead to a much greater inhibition of neurotransmitter release, and a greater disruption of hippocampus-dependent cognition, and perhaps result in much higher levels of anxiety in humans. Additionally, these pharmacological properties of the synthetic cannabinoids would result in much longer durations of action, compared to delta-9-THC, because of the higher potency. Ongoing studies are designed to look for "off site" effects of these compounds at non-cannabinoid receptor targets in the brain. Currently, we are evaluating potential interactions of these ligands with serotonin type 1 receptors in the cerebral cortex, as well as at calcium-activated potassium channels in the nucleus accumbens in rat brain slices. Preliminary data suggest that there may be actions of these synthetic cannabinoids at other molecular sites in the CNS.