Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia @NEST, Pisa, Italy.
Neuropsychopharmacology. 2011 Nov;36(12):2431-40. doi: 10.1038/npp.2011.129. Epub 2011 Jul 20.
Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme. Specifically, we measured basal cerebral blood volume (bCBV), an established correlate of basal metabolism, and assessed the reactivity of the dopaminergic system by mapping the pharmacological MRI (phMRI) response evoked by the dopamine-releaser amphetamine. Cocaine-exposed subjects exhibited reduced bCBV in fronto-cortical areas, nucleus accumbens, ventral hippocampus, and thalamus. The cocaine group also showed an attenuated functional response to amphetamine in ventrostriatal areas, an effect that was significantly correlated with total cocaine intake. An inverse relationship between bCBV in the reticular thalamus and the frontal response elicited by amphetamine was found in control subjects but not in the cocaine group, suggesting that the inhibitory interplay within this attentional circuit may be compromised by the drug. Importantly, histopathological analysis did not reveal significant alterations of the microvascular bed in the brain of cocaine-exposed subjects, suggesting that the imaging findings cannot be merely ascribed to cocaine-induced vascular damage. These results document that chronic, extended-access cocaine SA in the rat produces focal fronto-cortical and striatal alterations that serve as plausible neurobiological substrate for the behavioral expression of compulsive drug intake in laboratory animals.
可卡因成瘾通常在实验范式中进行建模，其中啮齿动物学会自行给药（SA）。然而，这些模型在多大程度上复制了可卡因成瘾的临床神经影像学研究中观察到的功能改变仍然未知。我们使用磁共振成像（MRI）来评估接受长期、扩展可卡因 SA 方案的大鼠的基础和诱发脑功能。具体来说，我们测量了基础脑血容量（bCBV），这是基础代谢的一个既定指标，并通过绘制多巴胺释放剂安非他命诱发的药理学 MRI（phMRI）反应来评估多巴胺系统的反应性。可卡因暴露的动物在前额皮质区域、伏隔核、腹侧海马体和丘脑显示出 bCBV 降低。可卡因组在纹状体区域对安非他命的功能反应也减弱，这种效应与可卡因总摄入量显著相关。在对照组中发现，网状丘脑的 bCBV 与安非他命诱发的额部反应之间存在反比关系，但在可卡因组中没有发现，这表明该注意力回路内的抑制相互作用可能因药物而受损。重要的是，组织病理学分析并未显示可卡因暴露动物大脑微血管床的明显改变，这表明成像结果不能仅仅归因于可卡因引起的血管损伤。这些结果表明，慢性、扩展的可卡因 SA 在大鼠中产生了局灶性额皮质和纹状体改变，这为实验室动物强迫性药物摄入的行为表达提供了合理的神经生物学基础。
