Molecular and Behavioral Neuroscience Institute.
Department of Psychiatry and Biobehavioral Science, Semel Institute for Neuroscience and Human Behavior, and Hatos Center for Neuropharmacology, University of California, Los Angeles, California 90095.
eNeuro. 2019 Feb 13;6(1). doi: 10.1523/ENEURO.0446-18.2019. eCollection 2019 Jan-Feb.
Estradiol potentiates behavioral sensitization to cocaine as well as self-administration of cocaine and other drugs of abuse in female rodents. Furthermore, stimulated dopamine (DA) in the dorsolateral striatum (DLS) is rapidly enhanced by estradiol, and it is hypothesized that this enhanced DA release mediates the more rapid escalation of drug taking seen in females, compared with males. The mechanisms mediating the effect of estradiol to enhance stimulated DA release were investigated in this study. Using microdialysis and high performance liquid chromatography coupled with electrochemical detection, we first examined the effect of estradiol on amphetamine-induced DA increase in the DLS of ovariectomized rats. We then tested whether the potentiation of this DA increase could be blocked by the estradiol receptor antagonist, ICI 182,780 (ICI), or an antagonist to the metabotropic glutamate receptor subtype 5 (mGlu5), 2-methyl-6-(phenylethynyl)pyridine (MPEP). There is evidence that estradiol receptors collaborate with mGlu5 within caveoli in DLS and mGlu5 is hypothesized to mediate many of the effects of estradiol in the addiction processes in females. Our data show that estradiol enhances the DA response to amphetamine. Either ICI or MPEP prevented the effect of estradiol to enhance DA release. Importantly, our results also showed that neither ICI or MPEP alone is able to influence the DA response to amphetamine when estradiol is not administrated, suggesting that ICI and MPEP act via estradiol receptors. Together, our findings demonstrate that estradiol potentiates amphetamine-stimulated DA release in the DLS and this effect requires both estradiol receptors and mGlu5.
雌二醇增强了雌性啮齿动物对可卡因的行为敏化作用以及可卡因和其他滥用药物的自我给药。此外，雌二醇迅速增强了背外侧纹状体（DLS）中的多巴胺（DA），并且假设这种增强的 DA 释放介导了与男性相比女性中更快的药物摄入增加。在这项研究中，研究了介导雌二醇增强刺激 DA 释放的作用的机制。使用微透析和高效液相色谱-电化学检测法，我们首先检查了雌二醇对去卵巢大鼠 DLS 中安非他命诱导的 DA 增加的影响。然后，我们测试了这种 DA 增加的增强是否可以被雌二醇受体拮抗剂 ICI 182,780（ICI）或代谢型谷氨酸受体亚型 5（mGlu5）拮抗剂 2-甲基-6-（苯乙炔基）吡啶（MPEP）阻断。有证据表明，雌二醇受体与 DLS 中的 caveoli 内的 mGlu5 协作，并且假设 mGlu5 介导雌二醇在女性成瘾过程中的许多作用。我们的数据表明，雌二醇增强了对安非他命的 DA 反应。ICI 或 MPEP 均可阻止雌二醇增强 DA 释放的作用。重要的是，我们的结果还表明，当未给予雌二醇时，ICI 或 MPEP 本身均不能影响安非他命对 DA 的反应，这表明 ICI 和 MPEP 通过雌二醇受体起作用。总之，我们的发现表明，雌二醇增强了 DLS 中安非他命刺激的 DA 释放，并且这种作用需要雌二醇受体和 mGlu5。
