Marinelli M, Aouizerate B, Barrot M, Le Moal M, Piazza P V
Psychobiologie des Comportements Adaptatifs, Institut National de la Santé et de la Recherche Médicale, Unité 259, Université de Bordeaux II, Domaine de Carreire, Rue Camille Saint-Saëns, 33077 Bordeaux cedex, France.
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7742-7. doi: 10.1073/pnas.95.13.7742.
Previous work has shown that glucocorticoid hormones facilitate the behavioral and dopaminergic effects of morphine. In this study we examined the possible role in these effects of the two central corticosteroid receptor types: mineralocorticoid receptor (MR), and glucocorticoid receptor (GR). To accomplish this, specific antagonists of these receptors were infused intracerebroventricularly and 2 hr later we measured: (i) locomotor activity induced by a systemic injection of morphine (2 mg/kg); (ii) locomotor activity induced by an infusion of morphine (1 microg per side) into the ventral tegmental area, which is a dopamine-dependent behavioral response to morphine; (iii) morphine-induced dopamine release in the nucleus accumbens, a dopaminergic projection site mediating the locomotor and reinforcing effects of drugs of abuse. Blockade of MRs by spironolactone had no significant effects on locomotion induced by systemic morphine. In contrast, blockade of GRs by either RU38486 or RU39305, which is devoid of antiprogesterone effects, reduced the locomotor response to morphine, and this effect was dose dependent. GR antagonists also reduced the locomotor response to intraventral tegmental area morphine as well as the basal and morphine-induced increase in accumbens dopamine, as measured by microdialysis in freely moving rats. In contrast, spironolactone did not modify dopamine release. In conclusion, glucocorticoids, via GRs, facilitate the dopamine-dependent behavioral effects of morphine, probably by facilitating dopamine release. The possibility of decreasing the behavioral and dopaminergic effects of opioids by an acute administration of GR antagonists may open new therapeutic strategies for treatment of drug addiction.
先前的研究表明，糖皮质激素可促进吗啡的行为和多巴胺能效应。在本研究中，我们考察了两种中枢糖皮质激素受体类型，即盐皮质激素受体（MR）和糖皮质激素受体（GR）在这些效应中可能发挥的作用。为实现这一目的，将这些受体的特异性拮抗剂脑室内注射，2小时后我们测量：（i）全身注射吗啡（2毫克/千克）诱导的运动活性；（ii）向腹侧被盖区注射吗啡（每侧1微克）诱导的运动活性，这是对吗啡的一种多巴胺依赖性行为反应；（iii）吗啡诱导的伏隔核多巴胺释放，伏隔核是介导滥用药物的运动和强化效应的多巴胺能投射部位。螺内酯阻断MRs对全身吗啡诱导的运动没有显著影响。相比之下，RU38486或无抗孕激素作用的RU39305阻断GRs可降低对吗啡的运动反应，且这种效应呈剂量依赖性。GR拮抗剂还可降低对腹侧被盖区注射吗啡的运动反应以及伏隔核多巴胺的基础水平和吗啡诱导的升高，这是通过对自由活动大鼠进行微透析测量的。相比之下，螺内酯不改变多巴胺释放。总之，糖皮质激素通过GRs促进吗啡的多巴胺依赖性行为效应，可能是通过促进多巴胺释放来实现的。急性给予GR拮抗剂降低阿片类药物的行为和多巴胺能效应的可能性，可能为药物成瘾的治疗开辟新的治疗策略。
