Yang Yang, Kocher Susan D, Lewis Mechelle M, Mailman Richard B
Department of Pharmacology, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States.
Translational Brain Research Center, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA, United States.
Front Neurosci. 2022 Jun 16;16:898051. doi: 10.3389/fnins.2022.898051. eCollection 2022.
Low doses of dopamine D agonists improve working memory-related behavior, but high doses eliminate the improvement, thus yielding an 'inverted-U' dose-response curve. This dose-dependency also occurs at the single neuron level in the prefrontal cortex where the cellular basis of working memory is represented. Because signaling mechanisms are unclear, we examined this process at the neuron population level. Two D agonists (2-methyldihydrexidine and CY208,243) having different signaling bias were tested in rats performing a spatial working memory-related T-maze task. 2-Methyldihydrexidine is slightly bias toward D-mediated β-arrestin-related signaling as it is a full agonist at adenylate cyclase and a super-agonist at β-arrestin recruitment, whereas CY208,243 is slightly bias toward D-mediated cAMP signaling as it has relatively high intrinsic activity at adenylate cyclase, but is a partial agonist at β-arrestin recruitment. Both compounds had the expected inverted U dose-dependency in modulating prefrontal neuronal activities, albeit with important differences. Although CY208,243 was superior in improving the strength of neuronal outcome sensitivity to the working memory-related choice behavior in the T-maze, 2-methyldihydrexidine better reduced neuron-to-neuron variation. Interestingly, at the neuron population level, both drugs affected the percentage, uniformity, and ensemble strength of neuronal sensitivity in a complicated dose-dependent fashion, but the overall effect suggested higher efficiency and potency of 2-methyldihydrexidine compared to CY208,243. The differences between 2-methyldihydrexidine and CY208,243 may be related to their specific D signaling. These results suggest that D-related dose-dependent regulation of working memory can be modified differentially by functionally selective ligands, theoretically increasing the balance between desired and undesired effects.
低剂量的多巴胺D受体激动剂可改善与工作记忆相关的行为，但高剂量则会消除这种改善效果，从而产生“倒U型”剂量反应曲线。这种剂量依赖性在工作记忆的细胞基础所在的前额叶皮层的单个神经元水平上也会出现。由于信号传导机制尚不清楚，我们在神经元群体水平上研究了这一过程。在执行与空间工作记忆相关的T迷宫任务的大鼠中测试了两种具有不同信号偏向性的D受体激动剂（2-甲基二氢麦角隐亭和CY208,243）。2-甲基二氢麦角隐亭对D介导的β-抑制蛋白相关信号传导略有偏向，因为它是腺苷酸环化酶的完全激动剂，也是β-抑制蛋白募集的超激动剂，而CY208,243对D介导的cAMP信号传导略有偏向，因为它在腺苷酸环化酶上具有相对较高的内在活性，但在β-抑制蛋白募集上是部分激动剂。两种化合物在调节前额叶神经元活动方面都具有预期的倒U型剂量依赖性，尽管存在重要差异。虽然CY208,243在提高神经元结果敏感性对T迷宫中与工作记忆相关的选择行为的强度方面更具优势，但2-甲基二氢麦角隐亭能更好地减少神经元之间的差异。有趣的是，在神经元群体水平上，两种药物都以复杂的剂量依赖性方式影响神经元敏感性的百分比、均匀性和整体强度，但总体效果表明2-甲基二氢麦角隐亭比CY208,243具有更高的效率和效力。2-甲基二氢麦角隐亭和CY208,243之间的差异可能与其特定的D信号传导有关。这些结果表明，与D相关的工作记忆剂量依赖性调节可以通过功能选择性配体进行不同的调节，从理论上讲，可以增加期望和非期望效应之间的平衡。
