The discriminative effects of the κ-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects
The discriminative effects of the κ-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects
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DOI：
10.1007/s00213-009-1771-5
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发表时间：
2010-06-01
影响因子：
3.4
通讯作者：
Kreek, Mary Jeanne
中科院分区：
文献类型：
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作者：
Butelman, Eduardo R.;Rus, Szymon;Kreek, Mary Jeanne
广泛使用的致幻剂salvinorin A是对κ-阿片受体具有选择性的植物衍生化合物的独特实例，并且可以产生与也在人类中滥用的具有经典致幻或解离性质的其他化合物不同的效果。本研究的目的是表征与人类具有高κ-受体遗传同源性的非人灵长类动物中的salvinorin A辨别线索。成年恒河猴（n = 10）和成年猴（n = 10）中的salvinorin A辨别线索。3）训练以区分鼠尾草素A（0.015mg/kg，s.c.）在食物强化的操作性辨别试验中，使用无条件行为终点（面部松弛和上睑下垂）的平行研究还评价了鼠尾草素A的κ-阿片受体介导的体内功能。训练猴子以区分鼠尾草素A的一般结构多样性、中枢穿透κ-激动剂（布马佐辛，U69，593和U 50，488）。相比之下，μ-和δ-阿片受体激动剂（芬太尼和SNC 80，分别）没有普遍化，也不是肾上腺素能5 HT 2致幻剂psilocybin或解离的N-甲基-D-天冬氨酸拮抗剂，氯胺酮。salvinorin A的辨别作用被阿片类拮抗剂quadazocine（0.32 mg/kg）阻断，但不被5 HT 2拮抗剂ketanserin（0.1 mg/kg）阻断。与这些发现一致，鼠尾草素和κ激动剂（例如，U69，593）在无条件终点（例如，这些发现支持以下结论：由鼠尾草素A产生的内感受性/辨别性线索是由κ受体的激动作用介导的，并且在机制上不同于由经典的多巴胺能致幻剂产生的内感受性/辨别性线索。
The widely available hallucinogen salvinorin A is a unique example of a plant-derived compound selective for kappa-opioid receptors and may produce effects distinct from those of other compounds with classic hallucinogenic or dissociative properties which are also abused in humans.The objective of this study is to characterize the salvinorin A discriminative cue in nonhuman primates with high kappa-receptor genetic homology to humans.Adult rhesus monkeys (n = 3) were trained to discriminate salvinorin A (0.015 mg/kg, s.c.) from vehicle, in a food-reinforced operant discrimination assay. Parallel studies, using unconditioned behavioral endpoints (facial relaxation and ptosis) also evaluated the kappa-opioid receptor mediation of salvinorin A in vivo function.Monkeys trained to discriminate salvinorin A generalized structurally diverse, centrally penetrating kappa-agonists (bremazocine, U69,593, and U50,488). By contrast, mu- and delta-opioid agonists (fentanyl and SNC80, respectively) were not generalized, nor were the serotonergic 5HT2 hallucinogen psilocybin or the dissociative N-methyl-D-aspartic acid antagonist, ketamine. The discriminative effects of salvinorin A were blocked by the opioid antagonist quadazocine (0.32 mg/kg), but not by the 5HT2 antagonist ketanserin (0.1 mg/kg). Consistent with these findings, salvinorin and kappa-agonists (e.g., U69,593) produce effects in the unconditioned endpoints (e.g., ptosis), whereas psilocybin was inactive.These findings support the conclusion that the interoceptive/discriminative cue produced by salvinorin A is mediated by agonism at kappa-receptors and is mechanistically distinct from that produced by a classic serotonergic hallucinogen.