Jayaram-Lindström N, Guterstam J, Häggkvist J, Ericson M, Malmlöf T, Schilström B, Halldin C, Cervenka S, Saijo T, Nordström A-L, Franck J
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Transl Psychiatry. 2017 Apr 25;7(4):e1104. doi: 10.1038/tp.2017.79.
The opioid antagonist naltrexone has been shown to attenuate the subjective effects of amphetamine. However, the mechanisms behind this modulatory effect are currently unknown. We hypothesized that naltrexone would diminish the striatal dopamine release induced by amphetamine, which is considered an important mechanism behind many of its stimulant properties. We used positron emission tomography and the dopamine D2-receptor radioligand [C]raclopride in healthy subjects to study the dopaminergic effects of an amphetamine injection after pretreatment with naltrexone or placebo. In a rat model, we used microdialysis to study the modulatory effects of naltrexone on dopamine levels after acute and chronic amphetamine exposure. In healthy humans, naltrexone attenuated the subjective effects of amphetamine, confirming our previous results. Amphetamine produced a significant reduction in striatal radioligand binding, indicating increased levels of endogenous dopamine. However, there was no statistically significant effect of naltrexone on dopamine release. The same pattern was observed in rats, where an acute injection of amphetamine caused a significant rise in striatal dopamine levels, with no effect of naltrexone pretreatment. However, in a chronic model, naltrexone significantly attenuated the dopamine release caused by reinstatement of amphetamine. Collectively, these data suggest that the opioid system becomes engaged during the more chronic phase of drug use, evidenced by the modulatory effect of naltrexone on dopamine release following chronic amphetamine administration. The importance of opioid-dopamine interactions in the reinforcing and addictive effects of amphetamine is highlighted by the present findings and may help to facilitate medication development in the field of stimulant dependence.
阿片类拮抗剂纳曲酮已被证明可减弱苯丙胺的主观效应。然而，这种调节作用背后的机制目前尚不清楚。我们推测纳曲酮会减少苯丙胺诱导的纹状体多巴胺释放，这被认为是其许多兴奋特性背后的重要机制。我们在健康受试者中使用正电子发射断层扫描和多巴胺D2受体放射性配体[C]雷氯必利，以研究在使用纳曲酮或安慰剂预处理后注射苯丙胺的多巴胺能效应。在大鼠模型中，我们使用微透析来研究纳曲酮对急性和慢性苯丙胺暴露后多巴胺水平的调节作用。在健康人类中，纳曲酮减弱了苯丙胺的主观效应，证实了我们之前的结果。苯丙胺使纹状体放射性配体结合显著减少，表明内源性多巴胺水平升高。然而，纳曲酮对多巴胺释放没有统计学上的显著影响。在大鼠中也观察到了相同的模式，急性注射苯丙胺导致纹状体多巴胺水平显著升高，纳曲酮预处理没有效果。然而，在慢性模型中，纳曲酮显著减弱了由苯丙胺复燃引起的多巴胺释放。总体而言，这些数据表明，在药物使用的更慢性阶段，阿片系统被激活，纳曲酮对慢性苯丙胺给药后多巴胺释放的调节作用证明了这一点。本研究结果突出了阿片-多巴胺相互作用在苯丙胺强化和成瘾作用中的重要性，可能有助于促进兴奋剂依赖领域的药物开发。
