DBSF and Neuroscience Center, University of Insubria, Busto Arsizio (VA), Italy.
Int J Neuropsychopharmacol. 2009 Jun;12(5):599-614. doi: 10.1017/S1461145708009371. Epub 2008 Sep 15.
Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and schizophrenia. Our studies showed that chronic-intermittent phencyclidine (PCP) treatment of rats, an animal model of schizophrenia-like cognitive deficit, impaired recognition memory in the novel object recognition (NOR) test and induced alterations in CB1 receptor functionality and in endocannabinoid levels mainly in the prefrontal cortex. In this region, we observed a significant reduction in GTPgammaS binding (-41%) accompanied by an increase in the levels of the endocannabinoid 2-AG (+38%) in PCP-treated rats, suggesting that a maladaptation of the endocannabinoid system might contribute to the glutamatergic-related cognitive symptoms encountered in schizophrenia disorders. Moreover, we evaluated the ability of the main psychoactive ingredient of marijuana, Delta9-tetrahydrocannabinol (THC), to modulate the cognitive dysfunctions and neuroadaptations in the endocannabinoid system induced by PCP. Chronic THC co-treatment worsened PCP-induced cognitive impairment, without inducing any effect per se, and in parallel, it provoked a severe reduction in the levels of the other endocannabinoid, AEA, vs. either vehicle (-73%) or PCP (-64%), whereas it reversed the PCP-induced increase in 2-AG levels. These results point to the involvement of the endocannabinoid system in this pharmacological model of cognitive dysfunction, with a potentially different role of AEA and 2-AG in schizophrenia-like behaviours and suggest that prolonged cannabis use might aggravate cognitive performances induced by chronic PCP by throwing off-balance the endocannabinoid system.
最近，大麻素的神经生物学方面的进展重新引起了人们对大麻与精神分裂症之间关联的兴趣。我们的研究表明，慢性间歇性苯环己哌啶（PCP）治疗大鼠，一种类似精神分裂症认知缺陷的动物模型，会损害新颖物体识别（NOR）测试中的识别记忆，并导致 CB1 受体功能和内源性大麻素水平发生变化，主要是在前额叶皮层。在这个区域，我们观察到 GTPγS 结合显著减少（-41%），同时内源性大麻素 2-AG 水平增加（+38%），这表明内源性大麻素系统的适应不良可能导致精神分裂症障碍中遇到的谷氨酸能相关认知症状。此外，我们评估了大麻的主要精神活性成分 Delta9-四氢大麻酚（THC）对 PCP 引起的认知功能障碍和内源性大麻素系统神经适应的调节能力。慢性 THC 共同治疗加重了 PCP 引起的认知障碍，而没有本身引起任何作用，并且平行地，它导致其他内源性大麻素 AEA 的水平严重降低，与载体相比（-73%）或 PCP（-64%），而它逆转了 PCP 引起的 2-AG 水平增加。这些结果表明内源性大麻素系统参与了这种认知功能障碍的药理学模型，AEA 和 2-AG 在类似精神分裂症的行为中可能具有不同的作用，并表明长期大麻使用可能通过使内源性大麻素系统失去平衡而加重慢性 PCP 引起的认知表现。
