Puighermanal Emma, Marsicano Giovanni, Busquets-Garcia Arnau, Lutz Beat, Maldonado Rafael, Ozaita Andrés
Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
Nat Neurosci. 2009 Sep;12(9):1152-8. doi: 10.1038/nn.2369. Epub 2009 Aug 2.
Cognitive impairment is one of the most important negative consequences associated with cannabis consumption. We found that CB1 cannabinoid receptor (CB1R) activation transiently modulated the mammalian target of rapamycin (mTOR)/p70S6K pathway and the protein synthesis machinery in the mouse hippocampus, which correlated with the amnesic properties of delta9-tetrahydrocannabinol (THC). In addition, non-amnesic doses of either the mTOR blocker rapamycin or the protein synthesis inhibitor anisomycin abrogated the amnesic-like effects of THC, pointing to a mechanism involving new protein synthesis. Moreover, using pharmacological and genetic tools, we found that THC long-term memory deficits were mediated by CB1Rs expressed on GABAergic interneurons through a glutamatergic mechanism, as both the amnesic-like effects and p70S6K phosphorylation were reduced in GABA-CB1R knockout mice and by NMDA blockade.
认知障碍是与大麻消费相关的最重要的负面后果之一。我们发现，CB1大麻素受体（CB1R）的激活会短暂调节雷帕霉素的哺乳动物靶点（mTOR）/p70S6K途径以及小鼠海马体中的蛋白质合成机制，这与Δ9-四氢大麻酚（THC）的失忆特性相关。此外，非失忆剂量的mTOR阻滞剂雷帕霉素或蛋白质合成抑制剂茴香霉素消除了THC的失忆样效应，表明存在一种涉及新蛋白质合成的机制。此外，使用药理学和遗传学工具，我们发现THC长期记忆缺陷是由GABA能中间神经元上表达的CB1R通过谷氨酸能机制介导的，因为在GABA-CB1R基因敲除小鼠中以及通过NMDA阻断，失忆样效应和p70S6K磷酸化均降低。
