Nicotine mitigates dopamine blockade-induced aberrant plasticity and learning

描述（由申请人提供）：流行病学研究一致表明，吸烟者帕金森病（PD）的发病率降低。然而，吸烟降低帕金森病发病率的机制尚不清楚。我们早期的研究表明，多巴胺（DA）阻断促进了抑制活动的增加，间接途径导致习得性运动抑制，这种现象我们称之为“异常运动学习”。在这个应用中，我们的目的是测试慢性尼古丁通过脱敏含有¿2的nachr，防止这种异常学习和减轻PD症状的假设。Specific Aim 1将分离DA神经元上的¿2失活是否足以阻止异常运动学习，以及含有¿2的nAChRs群体的特异性缺失是否阻止了在DA受体阻断期间异常学习的初始获得，或者在DA信号恢复后促进了新学习的获得。具体目标2将描述慢性尼古丁通过含¿2的nachr起作用，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释放，我们将检验这种适应性变化对DA阻断引起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.