Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy,
Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy.
J Neurosci. 2014 Sep 17;34(38):12716-24. doi: 10.1523/JNEUROSCI.1844-14.2014.
The progressive predominance of rewarding effects of addictive drugs over their aversive properties likely contributes to the transition from drug use to drug dependence. By inhibiting the activity of DA neurons in the VTA, GABA projections from the rostromedial tegmental nucleus (RMTg) are well suited to shift the balance between drug-induced reward and aversion. Since cannabinoids suppress RMTg inputs to DA cells and CB1 receptors affect alcohol intake in rodents, we hypothesized that the endocannabinoid system, by modulating this pathway, might contribute to alcohol preference. Here we found that RMTg afferents onto VTA DA neurons express CB1 receptors and display a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, that is, depolarization-induced suppression of inhibition (DSI). Next, we compared rodents with innate opposite alcohol preference, the Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. We found that DA cells from alcohol-naive sP rats displayed a decreased probability of GABA release and a larger DSI. This difference was due to the rate of 2-AG degradation. In vivo, we found a reduced RMTg-induced inhibition of putative DA neurons in sP rats that negatively correlated with an increased firing. Finally, alcohol failed to enhance RMTg spontaneous activity and to prolong RMTg-induced silencing of putative DA neurons in sP rats. Our results indicate functional modifications of RMTg projections to DA neurons that might impact the reward/aversion balance of alcohol attributes, which may contribute to the innate preference observed in sP rats and to their elevated alcohol intake.
成瘾性药物的奖赏效应逐渐占主导地位，而其厌恶特性逐渐减弱，这可能导致了从药物使用到药物依赖的转变。通过抑制 VTA 中的 DA 神经元的活性，来自 rostromedial tegmental nucleus（RMTg）的 GABA 投射非常适合改变药物引起的奖赏和厌恶之间的平衡。由于大麻素抑制 RMTg 对 DA 细胞的输入，而 CB1 受体影响啮齿动物的酒精摄入量，我们假设内源性大麻素系统通过调节这条通路，可能有助于酒精偏好。在这里，我们发现 VTA DA 神经元上的 RMTg 传入纤维表达 CB1 受体，并表现出依赖 2-花生四烯酸甘油（2-AG）的短期可塑性形式，即去极化诱导的抑制抑制（DSI）。接下来，我们比较了具有先天相反酒精偏好的大鼠，即撒丁岛酒精偏好（sP）和酒精非偏好（sNP）大鼠。我们发现，来自酒精未处理的 sP 大鼠的 DA 细胞显示 GABA 释放的概率降低和更大的 DSI。这种差异是由于 2-AG 降解的速度。在体内，我们发现 sP 大鼠中 RMTg 诱导的抑制作用减弱，这与放电增加呈负相关。最后，酒精未能增强 sP 大鼠中 RMTg 自发活动，并延长 RMTg 诱导的推定 DA 神经元沉默。我们的研究结果表明 RMTg 投射到 DA 神经元的功能发生了改变，这可能会影响酒精属性的奖赏/厌恶平衡，这可能有助于 sP 大鼠的先天偏好及其升高的酒精摄入量。
