Dolgetta Alexandra, Johnson Megan, Fruitman Kate, Siegel Luke, Zhou Yan, McEwen Bruce S, Kreek Mary Jeanne, Milner Teresa A
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA.
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
Neurobiol Stress. 2022 Jan 29;17:100431. doi: 10.1016/j.ynstr.2022.100431. eCollection 2022 Mar.
Glutamate receptors have a key role in the neurobiology of opioid addiction. Using electron microscopic immunocytochemical methods, this project elucidates how sex and chronic immobilization stress (CIS) impact the redistribution of GluN1 and GluA1 within rat hippocampal CA3 pyramidal cells following oxycodone (Oxy) conditioned place preference (CPP). Four groups of female and male Sprague-Dawley rats subjected to CPP were used: Saline- (Sal) and Oxy-injected (3 mg/kg, I.P.) naïve rats; and Sal- and Oxy-injected CIS rats. GluN1: In both naive and CIS rats, Sal-females compared to Sal-males had elevated cytoplasmic and total dendritic GluN1. Following Oxy CPP, near plasmalemmal, cytoplasmic, and total GluN1 decreased in CA3 dendrites of unstressed females suggesting reduced pools of GluN1 available for ligand binding. Following CIS, Oxy-males (which did not acquire CPP) had increased GluN1 in all compartments of dendrites and spines of CA3 neurons. GluA1: There were no differences in the distribution GluA1 in any cellular compartments of CA3 dendrites in naïve females and males following either Sal or Oxy CPP. CIS alone increased the percent of GluA1 in CA3 dendritic spines in males compared to females. CIS Oxy-males compared to CIS Sal-males had an increase in cytoplasmic and total dendritic GluA1. Thus, in CIS Oxy-males increased pools of GluN1 and GluA1 are available for ligand binding in CA3 neurons. Together with our prior experiments, these changes in GluN1 and GluA1 following CIS in males may contribute to an increased sensitivity of CA3 neurons to glutamate excitation and a reduced capacity to acquire Oxy CPP.
谷氨酸受体在阿片类药物成瘾的神经生物学中起着关键作用。本项目采用电子显微镜免疫细胞化学方法，阐明了性别和慢性固定应激（CIS）如何影响大鼠海马CA3锥体神经元中谷氨酸N1亚基（GluN1）和谷氨酸A1亚基（GluA1）在羟考酮（Oxy）条件性位置偏爱（CPP）后的重新分布。使用了四组接受CPP实验的雌性和雄性斯普拉格-道利大鼠：注射生理盐水（Sal）和注射Oxy（3mg/kg，腹腔注射）的未处理大鼠；以及注射Sal和注射Oxy的CIS大鼠。GluN1：在未处理大鼠和CIS大鼠中，与注射Sal的雄性大鼠相比，注射Sal的雌性大鼠细胞质和树突中GluN1总量升高。在Oxy CPP后，未受应激的雌性大鼠CA3树突中靠近质膜、细胞质和GluN1总量减少，表明可用于配体结合的GluN1池减少。在CIS后，注射Oxy的雄性大鼠（未形成CPP）CA3神经元树突和棘的所有区域中GluN1增加。GluA1：在未处理的雌性和雄性大鼠中，无论是注射Sal还是Oxy CPP后，CA3树突的任何细胞区域中GluA1的分布均无差异。单独的CIS使雄性大鼠CA3树突棘中GluA1的百分比高于雌性大鼠。与注射CIS Sal的雄性大鼠相比，注射CIS Oxy的雄性大鼠细胞质和树突中GluA1增加。因此，在注射CIS Oxy的雄性大鼠中，CA3神经元中有更多的GluN1和GluA1可用于配体结合。与我们之前的实验一起，雄性大鼠在CIS后GluN1和GluA1的这些变化可能导致CA3神经元对谷氨酸兴奋的敏感性增加以及获得Oxy CPP的能力降低。
