Vargas-Perez Hector, Minauro-Sanmiguel Fernando, Ting-A-Kee Ryan, Grieder Taryn Elizabeth, Méndez-Díaz Mónica, Prospéro-García Oscar, van der Kooy Derek
The Nierika Intercultural Medicine Institute, Ocuilan, Estado de México, 52483, Mexico; Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Postgrado En Ciencias Cognitivas, Universidad Autonoma Del Estado de Morelos, Cuernavaca, Mexico.
Unidad de Investigación Médica en Genética Humana, Hospital de Pediatría, Centro Médico Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.
Neurosci Lett. 2024 Jan 18;820:137597. doi: 10.1016/j.neulet.2023.137597. Epub 2023 Dec 16.
According to the opponent-process theory of drug addiction, the intake of an addictive substance initiates two processes: a rapid primary process that results in the drug's rewarding effects, and a slower opponent process that leads to the aversive motivational state of drug aftereffects. This aversive state is integral in the desire, pursuit, and maintenance of drug use, potentially leading to dependence and addiction. However, current observational and experimental evidence suggests that the administration of a 5-hydroxytryptamine receptors-type 2A (5-HT2A) agonist, while capable of inducing a positive mental state in humans, may not generate the behavioral patterns typically associated with drugs of abuse. In this study, we found that administering the 5-HT2A agonist 4-Acetoxy-N,N-dimethyltryptamine fumarate (4-AcO-DMT) did not result in place preference in male rats compared to control saline administration 24 h later, after the drug has been cleared from the organism. However, in a modified place preference test where only the acute motivational effects of the drug were evaluated (excluding withdrawal), 4-AcO-DMT was found to be rewarding. Furthermore, in another modified place preference test where only the motivational effects of drug withdrawal were evaluated (excluding the acute effects of drug administration), the 24-hour aftereffect of 5-HT2A agonist administration also resulted in a robust place preference. Therefore, while 4-AcO-DMT administration was able to induce place preference, its 24-hour aftereffect also produced a strong reward. In the counterbalanced test, this reward from the aftereffect effectively overshadowed its acute rewarding properties, which could potentially create a false impression that 4-AcO-DMT lacks motivational properties. This suggests that 5-HT2A agonist administration follows a different dynamic than that proposed by the opponent-process theory of motivation and implies that the administration of 5-HT2A agonists may lead to behavioral patterns less typical of drugs associated with addiction.
根据药物成瘾的对抗过程理论，摄入成瘾性物质会引发两个过程：一个快速的初级过程，产生药物的奖赏效应；以及一个较慢的对抗过程，导致药物后效应的厌恶动机状态。这种厌恶状态在药物使用的欲望、追求和维持中不可或缺，可能导致依赖和成瘾。然而，目前的观察和实验证据表明，给予5-羟色胺受体2A型（5-HT2A）激动剂，虽然能够在人类中诱导积极的精神状态，但可能不会产生通常与滥用药物相关的行为模式。在本研究中，我们发现，与24小时后给予对照生理盐水相比，给予5-HT2A激动剂富马酸4-乙酰氧基-N,N-二甲基色胺（4-AcO-DMT）不会导致雄性大鼠产生位置偏爱，此时药物已从机体中清除。然而，在一个仅评估药物急性动机效应（不包括戒断）的改良位置偏爱试验中，发现4-AcO-DMT具有奖赏性。此外，在另一个仅评估药物戒断动机效应（不包括药物给药的急性效应）的改良位置偏爱试验中，给予5-HT2A激动剂的24小时后效应也导致了强烈的位置偏爱。因此，虽然给予4-AcO-DMT能够诱导位置偏爱，但其24小时后效应也产生了强烈的奖赏作用。在平衡试验中，这种后效应产生的奖赏有效地掩盖了其急性奖赏特性，这可能会给人一种4-AcO-DMT缺乏动机特性的错误印象。这表明，给予5-HT2A激动剂遵循的动态过程不同于动机对抗过程理论所提出的，这意味着给予5-HT2A激动剂可能导致与成瘾相关药物不太典型的行为模式
