Department of Pharmacology and Addiction Research, Treatment & Training Center of Excellence, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Behav Pharmacol. 2024 Oct 1;35(7):378-385. doi: 10.1097/FBP.0000000000000787. Epub 2024 Jul 17.
There has been substantial and growing interest in the therapeutic utility of drugs acting at serotonin 2A subtype (5-HT 2A ) receptors, increasing the need for characterization of potential beneficial and adverse effects of such compounds. Although numerous studies have evaluated the possible rewarding and reinforcing effects of 5-HT 2A receptor agonists, there have been relatively few studies on potential aversive effects.
The current study investigated punishing effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in four rhesus monkeys responding under a choice procedure in which responding on one lever delivered a sucrose pellet alone and responding on the other lever delivered a sucrose pellet plus an intravenous infusion of a range of doses of fentanyl (0.1-3.2 µg/kg/infusion), histamine (3.2-100 µg/kg/infusion), or DOM (3.2-100 µg/kg/infusion).
When fentanyl was available, responding for a pellet plus an infusion increased dose dependently in all subjects, indicating a positive reinforcing effect of fentanyl. When histamine was available, responding for a pellet plus an infusion decreased in three of four subjects, indicating a punishing effect of histamine. Whether available before or after histamine, DOM did not systematically alter choice across the range of doses tested.
These results suggest that the 5-HT 2A receptor agonist DOM has neither positive reinforcing nor punishing effects under a choice procedure that is sensitive to both processes.
作用于血清素 2A 亚型（5-HT 2A）受体的药物具有显著且不断增长的治疗效用，这增加了对这些化合物潜在有益和不良影响进行特征描述的需求。尽管有许多研究评估了 5-HT 2A 受体激动剂可能具有的奖赏和强化作用，但关于潜在的厌恶作用的研究相对较少。
本研究在 4 只恒河猴中考察了 2,5-二甲氧基-4-甲基苯丙胺（DOM）的惩罚作用，这些猴子在一个选择程序下进行反应，在该程序中，对一个杠杆的反应单独提供一个蔗糖丸，而对另一个杠杆的反应则提供一个蔗糖丸和一系列剂量的芬太尼（0.1-3.2µg/kg/输注）、组胺（3.2-100µg/kg/输注）或 DOM（3.2-100µg/kg/输注）的静脉内输注。
当芬太尼可用时，所有受试者对药丸加输注的反应都呈剂量依赖性增加，表明芬太尼具有正强化作用。当组胺可用时，四个受试者中有三个对药丸加输注的反应减少，表明组胺具有惩罚作用。无论在组胺之前还是之后，DOM 在测试的剂量范围内都没有系统地改变选择。
这些结果表明，5-HT 2A 受体激动剂 DOM 在一种对两种过程均敏感的选择程序中既没有正强化作用也没有惩罚作用。
