Geranylgeranylacetone protects mice against morphine-induced hyperlocomotion, rewarding effect, and withdrawal syndrome

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• 作者：Fu-Cheng Luo^a ; ^b ; Lei Qi^b ; Tao Lv^b ; Sheng-Dong Wang^a ; Hua Liu^c ; Hajime Nakamura^d ; Junji Yodoi^e ; Jie Bai^b ; ^{jiebai662001@yahoo.com.cn}
• 关键词：GGA ; geranylgeranylacetone ; Trx-1 ; thioredoxin-1 ; Hsp70 ; heat shock protein 70 ; CREB ; cAMP-responsive element-binding protein ; Cdk5 ; cyclin-dependent kinase 5
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 期刊代码：105_08915849
• 类别：med
• 出版时间：1 April, 2012
• 卷：52
• 期：7
• 页码：1218-1227
• 文件大小：1112 K

摘要

There are few efficacious interventions to combat morphine dependence. Thioredoxin-1 (Trx-1) and heat shock protein 70 (Hsp70) are emerging as important modulators of neuronal function. They have been shown to be involved in cellular protective mechanisms against a variety of toxic stressors. This study was designed to investigate the effects of geranylgeranylacetone (GGA), a pharmacological inducer of Trx-1 and Hsp70, on morphine-induced hyperlocomotion, rewarding effect, and withdrawal syndrome. Trx-1 and Hsp70 expression was increased in the frontal cortex, hippocampus, ventral tegmental area, and nucleus accumbens of mice after GGA treatment. GGA administration reduced morphine-induced motor activity and inhibited conditioned place preference. GGA markedly attenuated the morphine-naloxone-induced withdrawal signs, including jumping, rearing, and forepaw tremor. Furthermore, the activation of cAMP-responsive element-binding protein and the expression of 螖FosB and cyclin-dependent kinase 5 were decreased in the nucleus accumbens by GGA treatment after morphine withdrawal. In the nucleus accumbens, GGA enhanced morphine-induced expression of Trx-1 and Hsp70 after morphine withdrawal. These results suggest that strengthening the expression of Trx-1 and Hsp70 in the brain by using noncytotoxic pharmacological inducers may provide a novel therapeutic strategy for morphine dependence. GGA could be a safe and novel therapeutic agent for morphine dependence.