Torrado Pacheco Alejandro, Olson Randall J, Garza Gabriela, Moghaddam Bita
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239.
Current address: Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109.
bioRxiv. 2023 Jan 9:2023.01.09.523291. doi: 10.1101/2023.01.09.523291.
Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the neural basis for this pattern of clinical efficacy, experimental and conceptual approaches that are different than traditional laboratory models of anxiety and depression are needed. A potential novel mechanism is that acute psilocybin improves cognitive flexibility, which then enhances the impact of clinician-assisted interventions. Consistent with this idea, we find that acute psilocybin robustly improves cognitive flexibility in male and female rats using a task where animals switched between previously learned strategies in response to uncued changes in the environment. Psilocybin did not influence Pavlovian reversal learning, suggesting that its cognitive effects are selective to enhanced switching between previously learned behavioral strategies. The serotonin (5HT) 2A receptor antagonist ketanserin blocked psilocybin's effect on set-shifting, while a 5HT2C-selective antagonist did not. Ketanserin alone also improved set-shifting performance, suggesting a complex relationship between psilocybin's pharmacology and its impact on flexibility. Further, the psychedelic drug 2,5-Dimethoxy-4-iodoamphetamine (DOI) impaired cognitive flexibility in the same task, suggesting that this effect of psilocybin does not generalize to all other serotonergic psychedelics. We conclude that the acute impact of psilocybin on cognitive flexibility provides a useful behavioral model to investigate its neuronal effects relevant to its positive clinical outcome.
已证明，与心理治疗或其他临床医生指导的干预措施相结合时，裸盖菇素可改善抑郁和焦虑症状。为了理解这种临床疗效模式的神经基础，需要采用不同于传统焦虑和抑郁实验室模型的实验和概念方法。一种潜在的新机制是，急性给予裸盖菇素可改善认知灵活性，进而增强临床医生辅助干预的效果。与此观点一致的是，我们发现，在一项任务中，雄性和雌性大鼠在环境中无提示变化时，需要在先前习得的策略之间进行切换，急性给予裸盖菇素能显著提高它们的认知灵活性。裸盖菇素并不影响巴甫洛夫式逆向学习，这表明其认知效应具有选择性，即增强先前习得的行为策略之间的切换。血清素（5-羟色胺，5HT）2A受体拮抗剂酮色林可阻断裸盖菇素对定势转换的作用，而5HT2C选择性拮抗剂则无此作用。单独使用酮色林也能改善定势转换表现，这表明裸盖菇素的药理学特性与其对灵活性的影响之间存在复杂关系。此外，致幻药物2,5-二甲氧基-4-碘苯丙胺（DOI）在同一任务中损害了认知灵活性，这表明裸盖菇素的这种作用并不适用于所有其他血清素能致幻剂。我们得出结论，裸盖菇素对认知灵活性的急性影响为研究其与积极临床结果相关的神经元效应提供了一个有用的行为模型。
