CB1 receptor blockade reduces the anxiogenic-like response and ameliorates the neurochemical imbalances associated with alcohol withdrawal in rats.
CB1 receptor blockade reduces the anxiogenic-like response and ameliorates the neurochemical imbalances associated with alcohol withdrawal in rats.
复制标题
CB1 受体阻断可减少大鼠的焦虑样反应并改善与酒精戒断相关的神经化学失衡。
DOI：
10.1016/j.neuropharm.2008.02.005
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发表时间：
2008
影响因子：
4.7
通讯作者：
Ramos,JoséA
中科院分区：
文献类型：
--
作者：
Rubio,Marina;Fernández-Ruiz,Javier;deMiguel,Rosario;Maestro,Begoña;MichaelWalker,J;Ramos,JoséA
有强有力的证据表明，阻断CB1受体可能会减少酒精依赖者的酒精摄入量。然而，仍有有限的证据表明CB1受体拮抗剂在减轻酒精戒断综合症方面可能也是有益的，尽管CB1受体基因敲除小鼠的酒精戒断似乎较温和。本实验研究了CB1受体拮抗剂利莫那班(SR141716)能否减轻慢性酒精暴露(饮水中7.2%，10天)所致的行为症状，逆转慢性酒精暴露3小时所致的神经化学失衡。给予利莫那班减弱了当常规酒精摄入中断时动物产生的强烈的焦虑性特征。这可能反映了接受利莫那班治疗的动物在涉及情绪(例如前额叶皮质)和运动(例如尾壳核和苍白球)反应的不同脑区形成的GABA/谷氨酸失衡的纠正。此外，利莫那班还影响了酒精戒断所产生的杏仁核和腹侧被盖区的多巴胺缺乏，尽管影响程度较小。然而，该拮抗剂不能纠正酒精戒断引起的5-羟色胺和神经肽Y的损伤。酒精戒断大鼠脑内的内源性大麻素活性表明，利莫那班引起的行为和神经化学改善与减弱酒精戒断可能引起的这种活性的增加无关。相反，在酒精戒断动物(如苍白球、黑质)中，CB1受体的密度降低，内源性大麻素和相关的N-酰乙醇胺(如杏仁核、尾壳核)的水平也降低。因此，利莫那班可能会增强通过中断正常饮酒而产生的内源性反应。总而言之，利莫那班可能会减轻与戒酒相关的戒断症状，这一效果可能是由于GABA和谷氨酸的正常化，在较小程度上是由于情感和运动相关区域的多巴胺传递。
There is strong evidence that blocking CB1receptors may reduce alcohol intake in alcohol-dependent individuals. However, there is still limited evidence that CB1receptor antagonists may also be beneficial in the attenuation of alcohol withdrawal syndrome, even though alcohol withdrawal appears to be milder in CB1receptor knockout mice. Here we have examined whether the CB1receptor antagonist rimonabant (SR141716) can alleviate the behavioral symptoms and revert the neurochemical imbalance elicited by a 3-h interruption of chronic alcohol exposure (7.2% in the drinking water for 10days) in male Wistar rats. Administration of rimonabant attenuated the strong anxiogenic traits of the animals that developed when regular alcohol intake was interrupted. This may reflect the correction of the GABA/glutamate imbalances developed by the animals that received rimonabant in various brain regions involved in emotional (e.g. prefrontal cortex) and motor (e.g. caudate-putamen and globus pallidus) responses. In addition, rimonabant also affected the dopamine deficits generated by alcohol abstinence in the amygdala and ventral-tegmental area, albeit to a lesser extent. However, this antagonist was unable to correct the impairment caused by alcohol abstinence in serotonin and neuropeptide Y. The endocannabinoid activity in the brain of alcohol-abstinent rats indicated that the behavioral and neurochemical improvements caused by rimonabant were not related to the attenuation of a possible increase in this activity generated by alcohol withdrawal. Conversely, the density of CB1receptors was reduced in alcohol-abstinent animals (e.g. globus pallidus, substantia nigra), as were the levels of endocannabinoids and related N-acylethanolamines (e.g. amygdala, caudate-putamen). Thus, rimonabant possibly enhances an endogenous response generated by interrupting the regular use of alcohol. In summary, rimonabant might attenuate withdrawal symptoms associated with alcohol abstinence, an effect that was presumably due to the normalization of GABA and glutamate, and to a lesser extent, dopamine transmission in emotion- and motor-related areas.