Yang Yang, Lee Sang-Min, Imamura Fumiaki, Gowda Krishne, Amin Shantu, Mailman Richard B
Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, 17033, USA.
Department of Neurology, Penn State University College of Medicine, Hershey, PA, 17033, USA.
Mol Psychiatry. 2021 Feb;26(2):645-655. doi: 10.1038/s41380-018-0312-1. Epub 2018 Dec 7.
Dopamine D agonists enhance cognition, but the role of different signaling pathways (e.g., cAMP or β-arrestin) is unclear. The current study compared 2-methyldihydrexidine and CY208,243, drugs with different degrees of both D intrinsic activity and functional selectivity. 2-Methyldihydrexidine is a full agonist at adenylate cyclase and a super-agonist at β-arrestin recruitment, whereas CY208,243 has relatively high intrinsic activity at adenylate cyclase, but much lower at β-arrestin recruitment. Both drugs decreased, albeit in dissimilar ways, the firing rate of neurons in prefrontal cortex sensitive to outcome-related aspects of a working memory task. 2-Methyldihydrexidine was superior to CY208,243 in prospectively enhancing similarity and retrospectively distinguishing differences between correct and error outcomes based on firing rates, enhancing the micro-network measured by oscillations of spikes and local field potentials, and improving behavioral performance. This study is the first to examine how ligand signaling bias affects both behavioral and neurophysiological endpoints in the intact animal. The data show that maximal enhancement of cognition via D activation occurred with a pattern of signaling that involved full unbiased intrinsic activity, or agonists with high β-arrestin activity.
多巴胺D激动剂可增强认知能力，但不同信号通路（如cAMP或β-抑制蛋白）的作用尚不清楚。本研究比较了2-甲基二氢麦角隐亭和CY208,243，这两种药物在D内在活性和功能选择性方面程度不同。2-甲基二氢麦角隐亭对腺苷酸环化酶是完全激动剂，对β-抑制蛋白募集是超级激动剂，而CY208,243在腺苷酸环化酶方面具有相对较高的内在活性，但在β-抑制蛋白募集方面则低得多。两种药物均降低了前额叶皮质中对工作记忆任务结果相关方面敏感的神经元的放电率，尽管方式不同。在基于放电率前瞻性地增强相似性以及回顾性地区分正确和错误结果之间的差异、增强通过尖峰振荡和局部场电位测量的微网络以及改善行为表现方面，2-甲基二氢麦角隐亭优于CY208,243。本研究首次探讨了配体信号偏向如何影响完整动物的行为和神经生理终点。数据表明，通过D激活实现认知的最大增强是通过一种涉及完全无偏向内在活性或具有高β-抑制蛋白活性的激动剂的信号模式。
