Dopamine-dependent responses to morphine depend on glucocorticoid receptors
Dopamine-dependent responses to morphine depend on glucocorticoid receptors
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DOI：
10.1073/pnas.95.13.7742
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发表时间：
1998-06-23
影响因子：
11.1
通讯作者：
Piazza, PV
中科院分区：
文献类型：
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作者：
Marinelli, M;Aouizerate, B;Piazza, PV
先前的研究表明，糖皮质激素促进吗啡的行为和多巴胺能效应。本研究探讨了两种中枢皮质激素受体：盐皮质激素受体（BIR）和糖皮质激素受体（GR）在上述效应中的可能作用。为此，侧脑室注射这两种受体的特异性拮抗剂，2小时后，我们测定了：（i）由全身注射吗啡（2 mg/kg）引起的自发活动;（ii）将吗啡（每侧1 μ g）注入腹侧被盖区诱导的运动活动，这是对吗啡的多巴胺依赖性行为反应;（iii）吗啡诱导的中脑核多巴胺释放，中脑核是介导运动和滥用药物的强化作用的多巴胺能投射部位。螺内酯阻断MR对全身吗啡诱导的运动无显著影响。与此相反，无论是RU 38486或RU 39305，这是缺乏抗孕酮作用的GR的封锁，减少了对吗啡的运动反应，这种效果是剂量依赖性的。GR拮抗剂也减少了运动反应腹侧被盖区吗啡以及基础和吗啡诱导的多巴胺的增加，通过微透析在自由活动的大鼠，相比之下，螺内酯没有修改多巴胺的释放。总之，糖皮质激素，通过GR，促进多巴胺依赖的行为效应的吗啡，可能是通过促进多巴胺的释放。通过急性给药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。
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 (BIR), and glucocorticoid receptor (GR), To accomplish this, specific antagonists of these receptors were infused intracerebroventricularly and 2 hr later,ve measured: (i) locomotor activity induced by a systemic injection of morphine (2 mg/kg); (ii) locomotor activity induced by an infusion of morphine (1 mu g 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.