Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland.
Nature. 2010 Feb 11;463(7282):769-74. doi: 10.1038/nature08758.
Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell-type-specific expression of alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.
苯二氮䓬类药物在临床上被广泛应用，也被滥用，但会使易成瘾人群成瘾。成瘾性药物会增加多巴胺的水平，并在中脑边缘奖赏系统中引发持久的突触适应，最终可能导致病理性行为。然而，苯二氮䓬类药物成瘾的神经基础仍然难以捉摸。在这里，我们发现苯二氮䓬类药物通过正调控附近中间神经元中的 GABA(A)（γ-氨基丁酸 A 型）受体来增加腹侧被盖区多巴胺神经元的放电。这种抑制作用依赖于这些细胞中表达的含有α1 的 GABA(A)受体，触发了多巴胺神经元上兴奋性传入的药物诱发的突触可塑性，并构成了药物强化。总之，我们的数据提供了证据表明，苯二氮䓬类药物通过腹侧被盖区中特定细胞类型表达的含有α1 的 GABA(A)受体，具有与成瘾性药物相同的药理学特征。这些数据还表明，亚单位选择性苯二氮䓬类药物避免了α1 的作用可能没有成瘾性。
