Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase.
Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase.
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DOI：
10.1038/npp.2010.127
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发表时间：
2010-11
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抗酒精中毒药物双硫兰(Antabuse)抑制乙醛脱氢酶(ALDH)，导致乙醇摄入时乙醛的积累，并产生令人反感的“反滥用反应”，阻止酒精消费。双硫兰也被证明可以阻止可卡因的使用，即使在没有与酒精相互作用的情况下，这表明存在一种不依赖ALDH的治疗机制。我们推测，双硫仑对多巴胺β羟基酶(DBH)的抑制是该药物治疗可卡因依赖的基础。我们测试了双硫仑对可卡因和食物自我给药行为的影响，以及药物诱导的可卡因寻找行为的恢复。然后，我们比较了双硫兰和选择性胸径激素抑制剂奈匹卡司的效果。双硫兰，剂量(100 mg/kg，ip)这使大脑去甲肾上腺素减少约40%，但不改变对食物或可卡因的固定比率1(FR1)的反应，而它完全阻止可卡因刺激(10 mg/kg，ip)。灭绝后毒品寻觅的恢复。小剂量的双硫仑(10 mg/kg)不降低去甲肾上腺素，对可卡因诱导的恢复没有影响。奈替卡司他概括了双硫仑(100 mg/kg)在剂量(50 mg/kg，i.p.)下的行为效应。这也导致了大脑NE的类似减少。胸径抑制不影响食物刺激下的觅食恢复。我们的结果表明，双硫仑治疗可卡因成瘾的疗效与抑制DBH和干扰环境刺激引发复发的能力有关。
The anti-alcoholism medication disulfiram (Antabuse) inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde upon ethanol ingestion and produces the aversive “Antabuse reaction” that deters alcohol consumption. Disulfiram has also been shown to deter cocaine use, even in the absence of an interaction with alcohol, indicating the existence of an ALDH-independent therapeutic mechanism. We hypothesized that disulfiram’s inhibition of dopamine β-hydroxylase (DBH), the catecholamine biosynthetic enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, underlies the drug’s ability to treat cocaine dependence. We tested the effects of disulfiram on cocaine and food self-administration behavior and drug-primed reinstatement of cocaine seeking in rats. We then compared the effects of disulfiram with those of the selective DBH inhibitor, nepicastat. Disulfiram, at a dose (100 mg/kg, i.p.) that reduced brain NE by ~40%, did not alter responding for food or cocaine on a fixed ratio 1 (FR1) schedule, whereas it completely blocked cocaine-primed (10 mg/kg, i.p.) reinstatement of drug seeking following extinction. A lower dose of disulfiram (10 mg/kg) that did not reduce NE had no effect on cocaine-primed reinstatement. Nepicastat recapitulated the behavioral effects of disulfiram (100 mg/kg) at a dose (50 mg/kg, i.p.) that produced a similar reduction in brain NE. Food-primed reinstatement of food seeking was not impaired by DBH inhibition. Our results suggest that disulfiram’s efficacy in the treatment of cocaine addiction is associated with the inhibition of DBH and interference with the ability of environmental stimuli to trigger relapse.
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影响因子：
--
作者：
Carroll, KM;Fenton, LR;Rounsaville, BJ
通讯作者：
Rounsaville, BJ
影响因子：
4.2
作者：
GRANT, BF;HARFORD, TC
通讯作者：
HARFORD, TC
影响因子：
9.3
作者：
Grassi, Maria Caterina;Cioce, Anna Maria;Nencini, Paolo
通讯作者：
Nencini, Paolo
影响因子：
10.6
作者：
Haile, CN;During, MJ;Kosten, TA
通讯作者：
Kosten, TA
影响因子：
10.6
作者：
George, TP;Chawarski, MC;Schottenfeld, RS
通讯作者：
Schottenfeld, RS