Experimental Psychology and Helmholtz Institute, Utrecht University, Utrecht, the Netherlands.
J Psychopharmacol. 2012 Apr;26(4):471-8. doi: 10.1177/0269881111431624. Epub 2012 Feb 20.
Preclinical evidence implicates several neurotransmitter systems in the extinction of conditioned fear. These results are of great interest, because the reduction of acquired fear associations is critical in therapies for anxiety disorders. We tested whether findings with respect to the N-methyl-D-aspartate (NMDA) and cannabinoid receptor (CB) systems in animals carry over to healthy human subjects. To that end, we administered selected doses of D-cycloserine (partial NMDA receptor agonist, 250 mg), delta-9-tetrahydrocannabinol (THC, CB(1) receptor agonist, 10 mg), or placebo prior to the extinction session of a 3-day conditioning protocol. D-cycloserine did not affect within-session extinction, or the retention of extinction in healthy human participants, in contrast with patient data but in line with previous reports in healthy volunteers. During extinction training, Δ9-THC reduced conditioned skin conductance responses, but not fear-potentiated startle. This effect was not retained at the retention test 2 days later, suggesting it was dependent on acute effects of the drug. Our findings implicate that facilitation of the CB(1) or NMDA system with the substances used in this study does not affect conditioned fear extinction lastingly in healthy humans. The apparent discrepancy between these findings and the results from (pre-)clinical trials is discussed in terms of room for improvement in these systems in healthy volunteers, and the lack of specificity of THC as a CB(1) agonist.
临床前证据表明，几种神经递质系统参与了条件性恐惧的消除。这些结果非常有趣，因为减少获得的恐惧联想对于焦虑障碍的治疗至关重要。我们测试了动物中 NMDA（N-甲基-D-天冬氨酸）和大麻素受体（CB）系统的发现是否适用于健康的人类受试者。为此，我们在为期 3 天的条件反射方案的消退阶段之前，给予选定剂量的 D-环丝氨酸（部分 NMDA 受体激动剂，250mg）、Δ9-四氢大麻酚（THC，CB1 受体激动剂，10mg）或安慰剂。与患者数据相反，但与健康志愿者的先前报告一致，D-环丝氨酸并未影响健康人类参与者的会话内消退或消退的保留。在消退训练期间，Δ9-THC 降低了条件性皮肤电导反应，但不增强惊吓反应。两天后的保留测试中没有保留这种效果，这表明它依赖于药物的急性作用。我们的研究结果表明，使用本研究中使用的物质促进 CB1 或 NMDA 系统不会在健康人群中持久地影响条件性恐惧的消退。这些发现与临床前试验的结果之间的明显差异，从健康志愿者中这些系统的改进空间以及 THC 作为 CB1 激动剂的缺乏特异性方面进行了讨论。
