Integrative Neuroscience Section, Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
Eur J Neurosci. 2009 Jul;30(2):272-8. doi: 10.1111/j.1460-9568.2009.06827.x. Epub 2009 Jul 15.
Mu opioid receptor (MOR) regulation of somatodendritic dopamine neurotransmission in the ventral tegmental area (VTA) was investigated using conventional microdialysis in freely moving rats and mice. Reverse dialysis of the MOR agonist DAMGO (50 and 100 microm) into the VTA of rats produced a concentration-dependent increase in dialysate dopamine concentrations. Basal dopamine overflow in the VTA was unaltered in mice lacking the MOR gene. However, basal gamma-aminobutyric acid (GABA) overflow in these animals was significantly increased, whereas glutamate overflow was decreased. Intra-VTA perfusion of DAMGO into wild-type (WT) mice increased dopamine overflow. GABA concentrations were decreased, whereas glutamate concentrations in the VTA were unaltered. Consistent with the loss of MOR, no effect of DAMGO was observed in MOR knockout (KO) mice. These data provide the first direct demonstration of tonically active MOR systems in the VTA that regulate basal glutamatergic and GABAergic neurotransmission in this region. We hypothesize that increased GABAergic neurotransmission following constitutive deletion of MOR is due to the elimination of a tonic inhibitory influence of MOR on GABAergic neurons in the VTA, whereas decreased glutamatergic neurotransmission in MOR KO mice is a consequence of intensified GABA tone on glutamatergic neurons and/or terminals. As a consequence, somatodendritic dopamine release is unaltered. Furthermore, MOR KO mice do not exhibit the positive correlation between basal dopamine levels and the glutamate/GABA ratio observed in WT mice. Together, our findings indicate a critical role of VTA MOR in maintaining an intricate balance between excitatory and inhibitory inputs to dopaminergic neurons.
在自由活动的大鼠和小鼠中，使用传统的微透析技术研究了 μ 阿片受体（MOR）对腹侧被盖区（VTA）树突体多巴胺神经传递的调节作用。MOR 激动剂 DAMGO（50 和 100 μm）逆行透析到大鼠的 VTA 中，导致透析液多巴胺浓度呈浓度依赖性增加。在缺乏 MOR 基因的小鼠中，VTA 中的基础多巴胺溢出没有改变。然而，这些动物的基础γ-氨基丁酸（GABA）溢出明显增加，而谷氨酸溢出减少。DAMGO 静脉内灌注到野生型（WT）小鼠的 VTA 中增加了多巴胺溢出。GABA 浓度降低，而 VTA 中的谷氨酸浓度不变。与 MOR 缺失一致，DAMGO 在 MOR 敲除（KO）小鼠中没有作用。这些数据首次直接证明 VTA 中存在持续活跃的 MOR 系统，该系统调节该区域的基础谷氨酸能和 GABA 能神经传递。我们假设，MOR 组成性缺失后 GABA 能神经传递的增加是由于 MOR 对 VTA 中 GABA 能神经元的持续抑制作用消除，而 MOR KO 小鼠中谷氨酸能神经传递减少是由于 GABA 对谷氨酸能神经元和/或末梢的紧张性影响增强所致。因此，树突体多巴胺释放没有改变。此外，MOR KO 小鼠没有表现出 WT 小鼠中观察到的基础多巴胺水平与谷氨酸/GABA 比值之间的正相关。总之，我们的研究结果表明，VTA MOR 在维持多巴胺能神经元兴奋性和抑制性输入之间的复杂平衡中起着关键作用。
