Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Department of Psychology, University of Massachusetts Boston, Boston, Massachusetts, United States of America.
PLoS One. 2021 Mar 1;16(3):e0247707. doi: 10.1371/journal.pone.0247707. eCollection 2021.
Adolescent psychostimulant abuse has been on the rise over the past decade. This trend has demonstrable ramifications on adolescent behavior and brain morphology, increasing risk for development of addiction during adolescence and in later adulthood. Neuroimmune substrates are implicated in the etiology of substance use disorders. To add to this body of work, the current study was developed to explore the role of a chemokine receptor, CXC Chemokine Receptor 4 (CXCR4), in the development of amphetamine (AMPH) sensitization. We targeted CXCR4 as it is implicated in developmental processes, dopaminergic transmission, neuroimmune responses, and the potentiation of psychostimulant abuse pathology. To evaluate the role of CXCR4 activity on the development of AMPH sensitization, a CXCR4 antagonist (Plerixafor; AMD3100) was administered to rats as a pretreatment variable. Specifically, adolescent Long Evans male rats (N = 37) were divided into four groups: (1) AMD3100 (IP, 4.0 mg/kg) + AMPH (IP, 4.0 mg/kg), (2) saline (SAL; 0.9% NaCl) + AMPH, (3) AMD3100 + SAL, and (4) SAL + SAL. Animals were first habituated to locomotor activity (LMA) chambers, then injected with a pretreatment drug (AMD3100 or SAL) followed by AMPH or SAL every other for four days. After a one-week withdrawal period, all animals were administered a low challenge dose of AMPH (IP, 1.0 mg/kg). AMPH-injected rats displayed significantly more locomotor activity compared to controls across all testing days. CXCR4 antagonism significantly attenuated AMPH-induced locomotor activity. On challenge day, AMD3100 pre-treated animals exhibited diminutive AMPH-induced locomotor activity compared to SAL pre-treated animals. Postmortem analyses of brain tissue revealed elevated CXCR4 protein levels in the striatum of all experimental groups. Our results implicate CXCR4 signaling in the development of AMPH sensitization and may represent an important therapeutic target for future research in psychostimulant abuse.
青少年滥用精神兴奋剂在过去十年中呈上升趋势。这种趋势对青少年的行为和大脑形态产生了明显的影响，增加了青少年和成年后期发展成瘾的风险。神经免疫底物与物质使用障碍的病因有关。为了增加这方面的研究，本研究旨在探讨趋化因子受体 CXC 趋化因子受体 4 (CXCR4) 在安非他命 (AMPH) 敏化发展中的作用。我们选择 CXCR4 作为研究对象，因为它与发育过程、多巴胺能传递、神经免疫反应以及增强精神兴奋剂滥用病理学有关。为了评估 CXCR4 活性对 AMPH 敏化发展的作用，我们将 CXCR4 拮抗剂 (plerixafor; AMD3100) 作为预处理变量给予大鼠。具体来说，将 37 只长耳雄性大鼠 (N = 37) 分为四组：(1) AMD3100 (IP，4.0 mg/kg) + AMPH (IP，4.0 mg/kg)，(2) 盐水 (SAL；0.9% NaCl) + AMPH，(3) AMD3100 + SAL 和 (4) SAL + SAL。动物首先适应 LMA 室，然后注射预处理药物 (AMD3100 或 SAL)，然后每隔一天注射 AMPH 或 SAL，共四天。经过一周的戒断期后，所有动物均给予低剂量 AMPH (IP，1.0 mg/kg) 挑战。与对照组相比，注射 AMPH 的大鼠在所有测试日的运动活性明显增加。CXCR4 拮抗作用显著减弱了 AMPH 诱导的运动活性。在挑战日，与 SAL 预处理的动物相比，AMD3100 预处理的动物的 AMPH 诱导的运动活性明显降低。大脑组织的死后分析显示，所有实验组的纹状体中 CXCR4 蛋白水平升高。我们的结果表明，CXCR4 信号在 AMPH 敏化的发展中起作用，可能是未来研究精神兴奋剂滥用的重要治疗靶点。
