Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
Neurobiol Learn Mem. 2011 Feb;95(2):206-20. doi: 10.1016/j.nlm.2011.01.002. Epub 2011 Jan 9.
Clinical and preclinical studies indicate that women and men differ in relapse vulnerability to drug-seeking behavior during abstinence periods. As relapse is frequently triggered by exposure of the recovered addict to objects previously associated with drug use and the formation of these associations requires memory systems engaged by the hippocampal formation (HF), studies exploring ovarian hormone modulation of hippocampal function are warranted. Previous studies revealed that ovarian steroids alter endogenous opioid peptide levels and trafficking of mu opioid receptors in the HF, suggesting cooperative interaction between opioids and estrogens in modulating hippocampal excitability. However, whether ovarian steroids affect the levels or trafficking of delta opioid receptors (DORs) in the HF is unknown. Here, hippocampal sections of adult male and normal cycling female Sprague-Dawley rats were processed for quantitative immunoperoxidase light microscopy and dual label fluorescence or immunoelectron microscopy using antisera directed against the DOR and neuropeptide Y (NPY). Consistent with previous studies in males, DOR-immunoreactivity (-ir) localized to select interneurons and principal cells in the female HF. In comparison to males, females, regardless of estrous cycle phase, show reduced DOR-ir in the granule cell layer of the dentate gyrus and proestrus (high estrogen) females, in particular, display reduced DOR-ir in the CA1 pyramidal cell layer. Ultrastructural analysis of DOR-labeled profiles in CA1 revealed that while females generally show fewer DORs in the distal apical dendrites of pyramidal cells, proestrus females, in particular, exhibit DOR internalization and trafficking towards the soma. Dual label studies revealed that DORs are found in NPY-labeled interneurons in the hilus, CA3, and CA1. While DOR colocalization frequency in NPY-labeled neuron somata was similar between animals in the hilus, proestrus females had fewer NPY-labeled neurons that co-labeled with DOR in stratum oriens of CA1 and CA3 when compared to males. Ultrastructural analysis of NPY-labeled axon terminals within stratum radiatum of CA1 revealed that NPY-labeled axon terminals contain DORs that are frequently found at or near the plasma membrane. As no differences were noted by sex or estrous cycle phase, DOR activation on NPY-labeled axon terminals would inhibit GABA release probability equally in males and females. Taken together, these findings suggest that ovarian steroids can impact hippocampal function through direct effects on DOR levels and trafficking in principal cells and broad indirect effects through reductions in DOR-ir in NPY-labeled interneurons, particularly in CA1.
临床和临床前研究表明，女性和男性在戒断期间对觅药行为的复发易感性存在差异。由于复发通常是由恢复的瘾君子接触以前与药物使用相关的物体引起的，并且这些关联的形成需要海马结构（HF）中参与的记忆系统，因此有必要研究卵巢激素对海马功能的调节。先前的研究表明，卵巢类固醇会改变 HF 中的内源性阿片肽水平和μ阿片受体的运输，这表明阿片类物质和雌激素在调节海马兴奋性方面具有协同作用。然而，卵巢类固醇是否会影响 HF 中δ阿片受体（DOR）的水平或运输尚不清楚。在这里，使用针对 DOR 和神经肽 Y（NPY）的抗血清，对成年雄性和正常发情周期雌性 Sprague-Dawley 大鼠的海马切片进行了定量免疫过氧化物酶光显微镜和双标记荧光或免疫电镜检查。与以前在雄性中的研究一致，DOR-免疫反应性（-ir）定位于雌性 HF 中的某些中间神经元和主细胞。与雄性相比，无论发情周期阶段如何，雌性的齿状回颗粒细胞层和发情前期（高雌激素）的雌性的 DOR-ir 均减少，特别是发情前期的雌性的 CA1 锥体细胞层的 DOR-ir 减少。CA1 中 DOR 标记的形态分析表明，尽管雌性通常在锥体细胞的远侧树突棘中显示较少的 DOR，但发情前期的雌性，特别是 DOR 内化并向胞体迁移。双标记研究表明，DOR 存在于门区、CA3 和 CA1 的 NPY 标记中间神经元中。尽管动物门区中 NPY 标记神经元胞体的 DOR 共定位频率相似，但与雄性相比，发情前期的雌性 CA1 和 CA3 的 CA1 层状或iens 中，NPY 标记的神经元与 DOR 共标记的神经元数量较少。CA1 层放射状层 NPY 标记轴突末端的超微结构分析表明，NPY 标记的轴突末端包含 DOR，DOR 经常位于或靠近质膜。由于没有观察到性别或发情周期阶段的差异，因此 DOR 激活 NPY 标记的轴突末端会以相同的方式抑制男性和女性的 GABA 释放概率。综上所述，这些发现表明，卵巢类固醇可以通过直接影响主细胞中的 DOR 水平和运输以及通过减少 NPY 标记的中间神经元中的 DOR-ir 产生广泛的间接影响，从而对海马功能产生影响，特别是在 CA1 中。
