Diazepam Inhibits Electrically Evoked and Tonic Dopamine Release in the Nucleus Accumbens and Reverses the Effect of Amphetamine
Diazepam Inhibits Electrically Evoked and Tonic Dopamine Release in the Nucleus Accumbens and Reverses the Effect of Amphetamine
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DOI：
10.1021/acschemneuro.6b00358
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发表时间：
2017-02-01
影响因子：
5
通讯作者：
Da Cunha, Claudio
中科院分区：
文献类型：
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作者：
Gomez-A, Alexander;Fiorenza, Amanda M.;Da Cunha, Claudio
安定是一种苯二氮卓类受体激动剂，具有抗焦虑和成瘾的特性。尽管大多数滥用药物会增加伏隔核中多巴胺的释放水平，但我们在这里表明，安定不仅会产生相反的作用，还能阻止苯丙胺促进多巴胺的释放。我们在碳纤维微电极上用20min取样、微透析和亚秒级快速扫描循环伏安记录显示，安定引起乌拉坦麻醉的成年雄性瑞士小鼠伏隔核紧张性和电诱导性多巴胺释放水平的剂量依赖性降低。在快速扫描循环伏安法中，电刺激腹侧被盖区可引起多巴胺的释放。我们观察到安定2 mg/kg和3 mg/kg可降低电诱发的多巴胺释放水平，而苯二氮类受体拮抗剂氟马西尼分别在2.5 mg/kg和5 mg/kg剂量下可逆转这种作用。没有观察到对多巴胺重新摄取的测量有显著影响。循环伏安实验进一步表明，苯丙胺(5 mg/kg，腹腔注射)可显著增加多巴胺的释放水平和再摄取的半衰期。安定(2 mg/kg)可显著减弱苯丙胺对多巴胺释放的影响，但不影响多巴胺的再摄取。这些结果提示，苯二氮卓类药物的药理作用中含有多巴胺能成分。此外，我们的发现挑战了所有滥用药物都会导致伏隔核多巴胺释放的经典观点，并表明苯二氮卓类药物可能有助于治疗对其他药物的成瘾，这些药物会增加多巴胺的释放水平，如可卡因、安非他明和尼古丁。
Diazepam is a benzodiazepine receptor agonist with anxiolytic and addictive properties. Although most drugs of abuse increase the level of release of dopamine in the nucleus accumbens, here we show that diazepam not only causes the opposite effect but also prevents amphetamine from enhancing dopamine release. We used 20 min sampling in vivo microdialysis and subsecond fast-scan cyclic voltammetry recordings at carbon-fiber microelectrodes to show that diazepam caused a dose-dependent decrease in the level of tonic and electrically evoked dopamine release in the nucleus accumbens of urethane-anesthetized adult male Swiss mice. In fast scan cyclic voltammetry assays, dopamine release was evoked by electrical stimulation of the ventral tegmental area. We observed that 2 and 3 mg of diazepam/kg reduced the level of electrically evoked dopamine release, and this effect was reversed by administration of the benzodiazepine receptor antagonist flumazenil in doses of 2.5 and 5 mg/kg, respectively. No significant effects on measures of dopamine re-uptake were observed. Cyclic voltammetry experiments further showed that amphetamine (5 mg/kg, intraperitoneally) caused a significant increase in the level of dopamine release and in the half-life for dopamine re-uptake. Diazepam (2 mg/kg) significantly weakened the effect of amphetamine on dopamine release without affecting dopamine re-uptake. These results suggest that the pharmacological effects of benzodiazepines have a dopaminergic component. In addition, our findings challenge the classic view that all drugs of abuse cause dopamine release in the nucleus accumbens and suggest that benzodiazepines could be useful in the treatment of addiction to other drugs that increase the level of dopamine release, such as cocaine, amphetamines, and nicotine.