Drew Michael R, Simpson Eleanor H, Kellendonk Christoph, Herzberg William G, Lipatova Olga, Fairhurst Stephen, Kandel Eric R, Malapani Chara, Balsam Peter D
Division of Integrative Neuroscience, Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
J Neurosci. 2007 Jul 18;27(29):7731-9. doi: 10.1523/JNEUROSCI.1736-07.2007.
The striatum receives prominent dopaminergic innervation that is integral to appetitive learning, performance, and motivation. Signaling through the dopamine D2 receptor is critical for all of these processes. For instance, drugs with high affinity for the D2 receptor potently alter timing of operant responses and modulate motivation. Recently, in an attempt to model a genetic abnormality encountered in schizophrenia, mice were generated that reversibly overexpress D2 receptors specifically in the striatum (Kellendonk et al., 2006). These mice have impairments in working memory and behavioral flexibility, components of the cognitive symptoms of schizophrenia, that are not rescued when D2 overexpression is reversed in the adult. Here we report that overexpression of striatal D2 receptors also profoundly affects operant performance, a potential index of negative symptoms. Mice overexpressing D2 exhibited impairments in the ability to time food rewards in an operant interval timing task and reduced motivation to lever press for food reward in both the operant timing task and a progressive ratio schedule of reinforcement. The motivational deficit, but not the timing deficit, was rescued in adult mice by reversing D2 overexpression with doxycycline. These results suggest that early D2 overexpression alters the organization of interval timing circuits and confirms that striatal D2 signaling in the adult regulates motivational process. Moreover, overexpression of D2 under pathological conditions such as schizophrenia and Parkinson's disease could give rise to motivational and timing deficits.
纹状体接受显著的多巴胺能神经支配，这对于奖赏学习、行为表现和动机至关重要。通过多巴胺D2受体进行的信号传导对所有这些过程都至关重要。例如，对D2受体具有高亲和力的药物会强烈改变操作性反应的时间并调节动机。最近，为了模拟精神分裂症中遇到的一种基因异常，研究人员培育出了在纹状体中特异性可逆性过表达D2受体的小鼠（凯伦登克等人，2006年）。这些小鼠在工作记忆和行为灵活性方面存在缺陷，而工作记忆和行为灵活性是精神分裂症认知症状的组成部分，在成年期D2过表达被逆转后，这些缺陷并未得到改善。在此我们报告，纹状体D2受体的过表达也会深刻影响操作性行为表现，这是阴性症状的一个潜在指标。过表达D2的小鼠在操作性间隔定时任务中对食物奖赏进行定时的能力存在缺陷，并且在操作性定时任务和渐进性比率强化程序中为获得食物奖赏而按压杠杆的动机降低。通过用强力霉素逆转D2过表达，成年小鼠的动机缺陷得到了改善，但定时缺陷并未改善。这些结果表明，早期D2过表达会改变间隔定时回路的组织，并证实成年期纹状体D2信号传导调节动机过程。此外，在精神分裂症和帕金森病等病理条件下D2的过表达可能会导致动机和定时缺陷。
