Renard Justine, Loureiro Michael, Rosen Laura G, Zunder Jordan, de Oliveira Cleusa, Schmid Susanne, Rushlow Walter J, Laviolette Steven R
Addiction Research Group, Department of Anatomy and Cell Biology, and.
Department of Anatomy and Cell Biology, and.
J Neurosci. 2016 May 4;36(18):5160-9. doi: 10.1523/JNEUROSCI.3387-15.2016.
Schizophrenia-related psychosis is associated with disturbances in mesolimbic dopamine (DA) transmission, characterized by hyperdopaminergic activity in the mesolimbic pathway. Currently, the only clinically effective treatment for schizophrenia involves the use of antipsychotic medications that block DA receptor transmission. However, these medications produce serious side effects leading to poor compliance and treatment outcomes. Emerging evidence points to the involvement of a specific phytochemical component of marijuana called cannabidiol (CBD), which possesses promising therapeutic properties for the treatment of schizophrenia-related psychoses. However, the neuronal and molecular mechanisms through which CBD may exert these effects are entirely unknown. We used amphetamine (AMPH)-induced sensitization and sensorimotor gating in rats, two preclinical procedures relevant to schizophrenia-related psychopathology, combined with in vivo single-unit neuronal electrophysiology recordings in the ventral tegmental area, and molecular analyses to characterize the actions of CBD directly in the nucleus accumbens shell (NASh), a brain region that is the current target of most effective antipsychotics. We demonstrate that Intra-NASh CBD attenuates AMPH-induced sensitization, both in terms of DAergic neuronal activity measured in the ventral tegmental area and psychotomimetic behavioral analyses. We further report that CBD controls downstream phosphorylation of the mTOR/p70S6 kinase signaling pathways directly within the NASh. Our findings demonstrate a novel mechanism for the putative antipsychotic-like properties of CBD in the mesolimbic circuitry. We identify the molecular signaling pathways through which CBD may functionally reduce schizophrenia-like neuropsychopathology.
The cannabis-derived phytochemical, cannabidiol (CBD), has been shown to have pharmacotherapeutic efficacy for the treatment of schizophrenia. However, the mechanisms by which CBD may produce antipsychotic effects are entirely unknown. Using preclinical behavioral procedures combined with molecular analyses and in vivo neuronal electrophysiology, our findings identify a functional role for the nucleus accumbens as a critical brain region whereby CBD can produce effects similar to antipsychotic medications by triggering molecular signaling pathways associated with the effects of classic antipsychotic medications. Specifically, we report that CBD can attenuate both behavioral and dopaminergic neuronal correlates of mesolimbic dopaminergic sensitization, via a direct interaction with mTOR/p70S6 kinase signaling within the mesolimbic pathway.
精神分裂症相关的精神病与中脑边缘多巴胺（DA）传递紊乱有关，其特征是中脑边缘通路多巴胺能活性过高。目前，精神分裂症唯一临床有效的治疗方法是使用阻断DA受体传递的抗精神病药物。然而，这些药物会产生严重的副作用，导致依从性差和治疗效果不佳。新出现的证据表明，大麻中一种名为大麻二酚（CBD）的特定植物化学成分与之有关，它对治疗精神分裂症相关的精神病具有潜在的治疗特性。然而，CBD发挥这些作用的神经元和分子机制完全未知。我们利用苯丙胺（AMPH）诱导的大鼠致敏和感觉运动门控，这两种与精神分裂症相关精神病理学相关的临床前程序，结合腹侧被盖区的体内单单位神经元电生理记录以及分子分析，来直接表征CBD在伏隔核壳（NASh）中的作用，NASh是目前大多数有效抗精神病药物的作用靶点。我们证明，NASh内注射CBD可减轻AMPH诱导的致敏，这在腹侧被盖区测量的多巴胺能神经元活动和拟精神病行为分析方面均有体现。我们进一步报告称，CBD直接在NASh内控制mTOR/p70S6激酶信号通路的下游磷酸化。我们的研究结果证明了CBD在中脑边缘回路中假定的抗精神病样特性的一种新机制。我们确定了CBD可能在功能上减轻精神分裂症样神经精神病理学的分子信号通路。
大麻衍生的植物化学成分大麻二酚（CBD）已被证明对精神分裂症的治疗具有药物治疗效果。然而，CBD产生抗精神病作用的机制完全未知。通过临床前行为程序结合分子分析和体内神经元电生理学，我们的研究结果确定了伏隔核作为一个关键脑区的功能作用，通过该脑区，CBD可以通过触发与经典抗精神病药物作用相关的分子信号通路，产生与抗精神病药物类似的效果。具体而言，我们报告称，CBD可以通过与中脑边缘通路内的mTOR/p70S6激酶信号直接相互作用，减轻中脑边缘多巴胺能致敏的行为和多巴胺能神经元相关性。
