Nicotine mitigates dopamine blockade-induced aberrant plasticity and learning

描述(由申请人提供)：流行病学研究一直表明，吸烟者帕金森氏病(PD)的发病率降低。然而，吸烟降低帕金森病发病率的机制仍不清楚。我们早期的研究表明，多巴胺(DA)的阻断促进了抑制的间接途径的活性增加，从而导致习得性运动抑制，我们将这种现象称为“异常运动学习”。在这项应用中，我们的目标是测试这一假设，即慢性尼古丁通过脱敏含有2-nAChRs，防止这种异常学习和减轻帕金森病症状。具体目标1将解开DA神经元上的2去激活是否足以阻止异常运动学习，以及这组含有2的nAChRs的特定缺失是否阻止了DA受体阻断期间异常学习的初始获得，还是促进了DA信号恢复后新学习的获得。具体目标2将描述慢性尼古丁通过含有nAChRs的作用阻止异常学习的机制。鉴于尼古丁在一段时间内显著改变DA的释放，我们将检验这样的适应性变化对DA阻断诱导的异常突触可塑性具有保护作用的假设。

DESCRIPTION (provided by applicant): Epidemiological studies have consistently shown that the incidence of Parkinson's disease (PD) is reduced in smokers. However, the mechanism by which smoking acts to reduce the incidence of PD remains unknown. Our earlier studies have demonstrated that dopamine (DA) blockade promotes increased activity of the inhibitory, indirect pathway leading to learned inhibition of movement, a phenomenon that we term 'aberrant motor learning.' In this application, we aim to test the hypothesis that chronic nicotine by desensitizing ¿2-containing nAChRs, prevents such aberrant learning and lessens PD symptoms. Specific Aim 1 will dissociate whether ¿2 deactivation on DA neurons is sufficient to block aberrant motor learning and whether the specific deletion of this population of ¿2-containing nAChRs prevents the initial acquisition of aberrant learning during DA receptor blockade or facilitates the acquisition of new learning once DA signaling is restored. Specific Aim 2 will delineate the mechanism by which chronic nicotine, acting via ¿2-containing nAChRs, blocks aberrant learning. Given that nicotine administered over a period of time significantly alters DA release, we will test the hypothesis that such adaptive changes have protective effects against aberrant synaptic plasticity induced by DA blockade.