Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California, United States of America.
PLoS One. 2012;7(7):e42365. doi: 10.1371/journal.pone.0042365. Epub 2012 Jul 31.
The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain ventral tegmental area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 23±3% of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABA(B) receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determine the local circuit mechanisms underlying VTA MOR reward.
阿片类药物奖赏的经典双神经元模型假设，μ 阿片受体（MOR）的激活通过抑制中脑腹侧被盖区（VTA）中的局部 GABA 能中间神经元来产生奖赏，从而使多巴胺神经元去抑制。尽管间接证据支持了该模型所提出的神经回路，但越来越多的证据表明 VTA 神经元的异质性以及最近的研究表明，MOR 激动剂抑制源自外源性神经元的 VTA 中的 GABA 能末梢，这对该模型的有效性提出了质疑。此外，VTA MOR 奖赏可以不依赖于多巴胺。为了直接检验 MOR 激活直接抑制局部 GABA 能神经元的假设，我们通过免疫细胞化学检测 GABA 或 GAD65/67 或原位杂交检测 GAD65/67 mRNA ，直接研究了用这些方法直接鉴定的大鼠 VTA GABA 神经元的特性。利用针对神经标记物 NeuN 的共标记和针对 GAD65/67 的原位杂交，我们发现 23±3%的 VTA 神经元为 GAD65/67(+)。与双神经元模型的假设相反，VTA GABA 能神经元在生理和药理学上均具有异质性。重要的是，只有 7/13 个被证实的 VTA GABA 神经元被 MOR 选择性激动剂 DAMGO 抑制。有趣的是，所有被证实的 VTA GABA 神经元均对 GABA(B)受体激动剂巴氯芬不敏感（0/6 个抑制），而所有被证实的多巴胺神经元均被抑制（19/19 个抑制）。我们在 VTA GABA 能神经元中发现的阿片类药物反应的异质性，以及源自 VTA 外神经元的 GABA 末梢被 MOR 激动剂抑制的事实，使得进一步的研究对于确定 VTA MOR 奖赏的局部回路机制至关重要。
