Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York.
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York.
Synapse. 2019 May;73(5):e22088. doi: 10.1002/syn.22088. Epub 2019 Jan 22.
In adult female, but not male, Sprague Dawley rats, chronic immobilization stress (CIS) increases mossy fiber (MF) Leu-Enkephalin levels and redistributes delta- and mu-opioid receptors (DORs and MORs) in hippocampal CA3 pyramidal cells and GABAergic interneurons to promote excitation and learning processes following subsequent opioid exposure. Here, we demonstrate that CIS females, but not males, acquire conditioned place preference (CPP) to oxycodone and that CIS "primes" the hippocampal opioid system in females for oxycodone-associated learning. In CA3b, oxycodone-injected (Oxy) CIS females relative to saline-injected (Sal) CIS females exhibited an increase in the cytoplasmic and total densities of DORs in pyramidal cell dendrites so that they were similar to Sal- and Oxy-CIS males. Consistent with our earlier studies, Sal- and Oxy-CIS females but not CIS males had elevated DOR densities in MF-CA3 dendritic spines, which we have previously shown are important for opioid-mediated long-term potentiation. In the dentate gyrus, Oxy-CIS females had more DOR-labeled interneurons than Sal-CIS females. Moreover, Sal- and Oxy-CIS females compared to both groups of CIS males had elevated levels of DORs and MORs in GABAergic interneuron dendrites, suggesting capacity for greater synthesis or storage of these receptors in circuits important for opioid-mediated disinhibition. However, more plasmalemmal MORs were on large parvalbumin-containing dendrites of Oxy-CIS males compared to Sal-CIS males, suggesting a limited ability for increased granule cell disinhibition. These results suggest that low levels of DORs in MF-CA3 synapses and hilar GABAergic interneurons may contribute to the attenuation of oxycodone CPP in males exposed to CIS.
在成年雌性而非雄性 Sprague Dawley 大鼠中，慢性束缚应激（CIS）会增加苔藓纤维（MF）亮氨酸脑啡肽水平，并重新分布海马 CA3 锥体神经元和 GABA 能中间神经元中的 δ 型和 μ 型阿片受体（DOR 和 MOR），以促进随后接触阿片类药物后的兴奋和学习过程。在这里，我们证明 CIS 雌性而非雄性会对羟考酮产生条件性位置偏爱（CPP），并且 CIS 会使雌性的海马阿片系统对羟考酮相关学习产生“启动”作用。在 CA3b 中，与生理盐水注射（Sal）CIS 雌性相比，羟考酮注射（Oxy）CIS 雌性的锥体神经元树突中的细胞质和总 DOR 密度增加，使其类似于 Sal 和 Oxy-CIS 雄性。与我们之前的研究一致，Sal 和 Oxy-CIS 雌性而非 CIS 雄性在 MF-CA3 树突棘中有更高的 DOR 密度，我们之前已经表明这对于阿片介导的长时程增强很重要。在齿状回中，Oxy-CIS 雌性比 Sal-CIS 雌性有更多的 DOR 标记的中间神经元。此外，与 CIS 雄性的两组相比，Sal 和 Oxy-CIS 雌性在 GABA 能中间神经元树突中具有更高水平的 DOR 和 MOR，这表明在阿片介导的抑制解除中，这些受体在重要回路中有更大的合成或储存能力。然而，与 Sal-CIS 雄性相比，Oxy-CIS 雄性中有更多的质膜 MOR 位于大的含有 parvalbumin 的树突上，这表明增加颗粒细胞抑制解除的能力有限。这些结果表明，暴露于 CIS 后，MF-CA3 突触和海马 GABA 能中间神经元中低水平的 DOR 可能导致羟考酮 CPP 减弱。
