Department of Behavioral Neuroscience and Drug Development, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Department of Philosophy, Institute of Sociology, Jagiellonian University, Kraków, Poland.
J Psychopharmacol. 2023 Nov;37(11):1149-1156. doi: 10.1177/02698811231205692. Epub 2023 Oct 16.
In clinical studies, psychedelics including psilocybin and D-lysergic acid diethylamide (LSD) demonstrate rapid and persistent antidepressant effects. Since the effective treatment with psychedelics is usually provided with psychotherapy, it is debatable whether their prolonged efficacy can be observed in infrahuman species. Preclinical reports on psychedelics' effects most often address their acute actions, and different tests and models provide inconsistent results. The goal of this study was to examine whether the treatment with psilocybin and/or LSD would demonstrate immediate and/or sustained antidepressant-like effects in the differential reinforcement of low-rate responding (DRL) schedule in rats. In contrast to the antidepressant screening tools, the DRL 72s test is known to detect antidepressants with high predictive validity as it differentiates clinically effective antidepressants from other psychoactive drugs in non-stressed animals.
Adult male Sprague Dawley rats were injected over three consecutive days with psilocybin (1 mg/kg), LSD (0.08 mg/kg), or saline and then tested in DRL 72s for the following 4 weeks.
Treatment with psilocybin but not LSD demonstrated an immediate antidepressant-like effect, manifested as an increased number of reinforced presses and response efficiency. By contrast, neither of the drugs showed a long-term (up to 4 weeks following administration) antidepressant-like effect.
Using DRL 72s schedule of reinforcement, we demonstrated the acute antidepressant-like effect of psilocybin but not of LSD, and failed to detect their persistent antidepressant-like efficacy. The present study suggests that the detection of long-lasting antidepressant-like activity in rats could be challenging and may require entirely novel behavioral methods.
在临床研究中，包括裸盖菇素和 D-麦角酸二乙酰胺（LSD）在内的迷幻剂显示出快速和持久的抗抑郁作用。由于迷幻剂的有效治疗通常需要结合心理治疗，因此它们在非人类物种中是否能观察到延长的疗效仍存在争议。关于迷幻剂作用的临床前报告大多涉及它们的急性作用，不同的测试和模型提供了不一致的结果。本研究的目的是检验裸盖菇素和/或 LSD 的治疗是否会在大鼠的区分性低频率反应强化（DRL）时间表中表现出即时和/或持续的抗抑郁样效应。与抗抑郁药筛选工具不同，DRL 72s 测试以其能够区分临床有效的抗抑郁药与非应激动物中的其他精神活性药物而闻名，是一种能够检测抗抑郁药的有效方法。
成年雄性 Sprague Dawley 大鼠连续三天接受裸盖菇素（1mg/kg）、LSD（0.08mg/kg）或生理盐水注射，然后在 DRL 72s 中进行测试，为期 4 周。
裸盖菇素治疗而非 LSD 治疗表现出即时的抗抑郁样效应，表现为增加的强化按压次数和反应效率。相比之下，两种药物均未显示出长期（给药后长达 4 周）的抗抑郁样效应。
使用 DRL 72s 强化时间表，我们证明了裸盖菇素而非 LSD 的急性抗抑郁样效应，并且未能检测到它们的持久抗抑郁样功效。本研究表明，在大鼠中检测到持久的抗抑郁样活性可能具有挑战性，并且可能需要全新的行为方法。
