Identification of rat ventral tegmental area GABAergic neurons.
Identification of rat ventral tegmental area GABAergic neurons.
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DOI：
10.1371/journal.pone.0042365
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Fields HL
中科院分区：
文献类型：
--
作者：
Margolis EB;Toy B;Himmels P;Morales M;Fields HL
典型的阿片样物质奖励双神经元模型认为，mu阿片样物质受体（MOR）激活通过抑制局部gaba能中间神经元，解除对中脑腹侧被盖区（VTA）多巴胺神经元的抑制，从而产生奖励。尽管间接证据支持该模型所假设的神经回路，但由于越来越多的证据表明VTA神经元异质性，以及最近MOR激动剂抑制外源神经元在VTA中产生的gaba能终端，该模型的有效性受到了质疑。此外，VTA more奖励可能与多巴胺无关。为了直接验证MOR激活直接抑制局部GABA能神经元的假设，我们研究了用GABA或GAD65/67的免疫细胞化学或GAD65/67 mRNA的原位杂交直接鉴定的大鼠VTA GABA神经元的特性。利用神经标记物NeuN的抗体共标记和GAD65/67的原位杂交，我们发现23±3%的VTA神经元是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都是异质的。重要的是，只有7/13证实VTA GABA神经元被MOR选择性激动剂DAMGO抑制。有趣的是，所有确认的VTA GABA神经元对GABAB受体激动剂巴氯芬不敏感（0/6抑制），而所有确认的多巴胺神经元均被抑制（19/19）。我们在VTA GABA能神经元中发现的阿片反应的异质性，以及VTA外神经元产生的GABA终端被MOR激动剂抑制的事实，使得进一步研究确定VTA MOR奖励的局部电路机制至关重要。
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 GABAB 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.
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影响因子：
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作者：
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