Niwa Minae, Nitta Atsumi, Yamada Kiyofumi, Nabeshima Toshitaka
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
J Pharmacol Sci. 2007 Jun;104(2):116-21. doi: 10.1254/jphs.cp0070017. Epub 2007 May 31.
There are few efficacious medications for drug dependence at present. Recent evidence has suggested that various cytokines are involved in the effects of abused drugs, suggesting that these factors play a role in drug dependence. In this article, the roles of glial cell line-derived neurotrophic factor (GDNF) and tumor necrosis factor-alpha (TNF-alpha) in drug dependence are discussed. GDNF inhibits the cocaine-induced upregulation of tyrosine hydroxylase activity in the ventral tegmental area and blocks behavioral responses to cocaine. TNF-alpha attenuates rewarding effects and locomotor sensitization induced by methamphetamine (METH) and morphine (MOR). Moreover, we mentioned the potential of Leu-Ile, which induces the expression of GDNF and TNF-alpha, as a novel therapeutic agent for drug dependence. Leu-Ile inhibits not only the development but also the maintenance of METH- or MOR-induced place preference and locomotor sensitization in mice. The inhibitory effect of Leu-Ile on METH- or MOR-induced place preference is not observed in GDNF heterozygous and TNF-alpha knockout mice. Leu-Ile inhibits METH- or MOR-induced place preference and sensitization by attenuating the METH- or MOR-induced increase in extracellular dopamine levels in the nucleus accumbens via the induction of GDNF and TNF-alpha expression. These findings suggest that Leu-Ile could be a novel therapeutic agent for drug dependence.
目前用于治疗药物依赖的有效药物很少。最近的证据表明，多种细胞因子参与了滥用药物的作用，这表明这些因素在药物依赖中发挥作用。在本文中，我们讨论了胶质细胞源性神经营养因子（GDNF）和肿瘤坏死因子-α（TNF-α）在药物依赖中的作用。GDNF可抑制可卡因诱导的腹侧被盖区酪氨酸羟化酶活性上调，并阻断对可卡因的行为反应。TNF-α可减弱甲基苯丙胺（METH）和吗啡（MOR）诱导的奖赏效应和运动敏化。此外，我们提到了亮氨酸-异亮氨酸（Leu-Ile）作为一种新型药物依赖治疗剂的潜力，它可诱导GDNF和TNF-α的表达。Leu-Ile不仅抑制小鼠中METH或MOR诱导的位置偏爱和运动敏化的形成，还抑制其维持。在GDNF杂合子和TNF-α基因敲除小鼠中未观察到Leu-Ile对METH或MOR诱导的位置偏爱的抑制作用。Leu-Ile通过诱导GDNF和TNF-α的表达，减弱METH或MOR诱导的伏隔核细胞外多巴胺水平升高，从而抑制METH或MOR诱导的位置偏爱和敏化。这些发现表明，Leu-Ile可能是一种新型的药物依赖治疗剂。
