Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Dr, Malott Hall, Room 5040, Lawrence, KS, USA; Consortium for Translational Research on Aggression and Drug Abuse (ConTRADA), University of Kansas, Lawrence (KS), USA.
"Guy Everett" Laboratory, Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Italy.
Eur Neuropsychopharmacol. 2014 Jun;24(6):974-85. doi: 10.1016/j.euroneuro.2013.12.011. Epub 2014 Jan 18.
Cannabis abuse in adolescence is associated with a broad array of phenotypical consequences, including a higher risk for schizophrenia and other mental disturbances related to dopamine (DA) imbalances. The great variability of these sequelae likely depends on the key influence of diverse genetic vulnerability factors. Inbred rodent strains afford a highly informative tool to study the contribution of genetic determinants to the long-term effects of juvenile cannabinoid exposure. In this study, we analyzed the phenotypical impact of the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 2mg/kg/day from postnatal day 35-48) in adolescent Lewis rats, an inbred strain exhibiting resistance to psychotomimetic effects of environmental manipulations. At the end of this treatment, WIN-injected animals displayed increased survival of new cells (mainly oligodendroglia precursors) in the striatum and prefrontal cortex (PFC), two key terminal fields of DAergic pathways. To test whether these changes may be associated with enduring behavioral alterations, we examined the consequences of adolescent WIN treatment in adulthood (postnatal days 60-70), with respect to DA levels and metabolism as well as multiple behavioral paradigms. Rats injected with WIN exhibited increased turnover, but not levels, of striatal DA. In addition, cannabinoid-treated animals displayed increases in acoustic startle latency and novel-object exploration; however, WIN treatment failed to induce overt deficits of sensorimotor gating and social interaction. These results indicate that, in Lewis rats, juvenile cannabinoid exposure leads to alterations in frontostriatal gliogenesis, as well as select behavioral alterations time-locked to high DAergic metabolism, but not overt schizophrenia-related deficits.
青少年滥用大麻与广泛的表型后果有关，包括精神分裂症和其他与多巴胺（DA）失衡相关的精神障碍的风险增加。这些后遗症的巨大变异性可能取决于不同遗传易感性因素的关键影响。近交系啮齿动物品系为研究遗传决定因素对青少年大麻素暴露的长期影响提供了一个非常有信息价值的工具。在这项研究中，我们分析了合成大麻素激动剂 WIN 55,212-2（WIN；从出生后第 35-48 天每天 2mg/kg）在青少年 Lewis 大鼠中的表型影响，这是一种近交系，对环境操作的致幻作用具有抗性。在治疗结束时，WIN 注射动物在纹状体和前额叶皮层（PFC）中表现出新生细胞（主要是少突胶质细胞前体）存活增加，这两个区域是 DA 能途径的关键末端区域。为了测试这些变化是否与持久的行为改变有关，我们在成年期（出生后第 60-70 天）检查了青少年 WIN 治疗的后果，涉及 DA 水平和代谢以及多种行为范式。接受 WIN 注射的大鼠表现出纹状体 DA 周转率增加，但水平不变。此外，大麻素处理的动物表现出听觉惊跳潜伏期和新物体探索增加；然而，WIN 处理未能诱导明显的感觉运动门控和社会互动缺陷。这些结果表明，在 Lewis 大鼠中，青少年大麻素暴露导致额纹状体神经发生改变，以及与高 DA 代谢相关的选择性行为改变，但没有明显的与精神分裂症相关的缺陷。
