The Adelson Center for the Biology of Addictive Diseases and The Mauerberger Chair in Neuropharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
Exp Brain Res. 2012 Sep;221(4):437-48. doi: 10.1007/s00221-012-3186-5. Epub 2012 Jul 22.
We have previously reported that a single injection of an ultra-low dose of delta-9-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) protected the brain from pentylenentetrazole (PTZ)-induced cognitive deficits when applied 1-7 days before or 1-3 days after the insult. In the present study we expanded the protective profile of THC by showing that it protected mice from cognitive deficits that were induced by a variety of other neuronal insults, including pentobarbital-induced deep anesthesia, repeated treatment with 3,4 methylenedioxymethamphetamine (MDMA; "ecstasy") and exposure to carbon monoxide. The protective effect of THC lasted for at least 7 weeks. The same ultra-low dose of THC (0.002 mg/kg, a dose that is 3-4 orders of magnitude lower than the doses that produce the known acute effects of the drug in mice) induced long-lasting (7 weeks) modifications of extracellular signal-regulated kinase (ERK) activity in the hippocampus, frontal cortex and cerebellum of the mice. The alterations in ERK activity paralleled changes in its activating enzyme MEK and its inactivating enzyme MKP-1. Furthermore, a single treatment with the low dose of THC elevated the level of pCREB (phosphorylated cAMP response element-binding protein) in the hippocampus and the level of BDNF (brain-derived neurotrophic factor) in the frontal cortex. These long-lasting effects indicate that a single treatment with an ultra-low dose of THC can modify brain plasticity and induce long-term behavioral and developmental effects in the brain.
我们之前曾报道过，单次注射极低剂量的 delta-9-四氢大麻酚（THC；大麻的精神活性成分），可在损伤前 1-7 天或损伤后 1-3 天内，预防戊四氮（PTZ）诱导的认知缺陷。在本研究中，我们通过证明 THC 可预防各种其他神经元损伤诱导的认知缺陷，包括戊巴比妥诱导的深度麻醉、重复使用 3,4-亚甲二氧基甲基苯丙胺（MDMA；“摇头丸”）和暴露于一氧化碳，扩大了 THC 的保护范围。THC 的保护作用至少持续 7 周。相同的超低剂量 THC（0.002mg/kg，该剂量比在小鼠中产生药物已知急性作用的剂量低 3-4 个数量级）诱导了小鼠海马体、额叶皮质和小脑细胞外信号调节激酶（ERK）活性的持久（7 周）改变。ERK 活性的改变与它的激活酶 MEK 和失活酶 MKP-1 的改变平行。此外，单次低剂量 THC 处理可提高海马体中 pCREB（磷酸化 cAMP 反应元件结合蛋白）的水平和前额皮质中 BDNF（脑源性神经营养因子）的水平。这些持久的影响表明，单次超低剂量的 THC 处理可以改变大脑的可塑性，并在大脑中诱导长期的行为和发育影响。
