Department of Psychology, California State University, San Bernardino, California.
Department of Psychology, University of Kentucky, Lexington, Kentucky.
J Neurosci Res. 2019 Dec;97(12):1546-1558. doi: 10.1002/jnr.24491. Epub 2019 Jul 15.
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which irreversibly inactivates dopamine (DA) receptors, causes pronounced age-dependent behavioral effects in rats. For example, EEDQ either augments or does not affect the DA agonist-induced locomotor activity of preweanling rats while attenuating the locomotion of adolescent and adult rats. The twofold purpose of this study was to determine whether EEDQ would: (a) potentiate or attenuate the cocaine-induced locomotor activity of preweanling, adolescent, and adult rats; and (b) alter the sensitivity of surviving D2 receptors. Rats were treated with vehicle or EEDQ (2.5 or 7.5 mg/kg) on postnatal day (PD) 17, PD 39, and PD 84. In the behavioral experiments, saline- or cocaine-induced locomotion was assessed 24 hr later. In the biochemical experiments, dorsal striatal samples were taken 24 hr after vehicle or EEDQ treatment and later assayed for NPA-stimulated GTPγS receptor binding, G protein-coupled receptor kinase 6 (GRK6), and β-arrestin-2 (ARRB2). GTPγS binding is a direct measure of ligand-induced G protein activation, while GRK6 and ARRB2 modulate the internalization and desensitization of D2 receptors. Results showed that EEDQ potentiated the locomotor activity of preweanling rats, while attenuating the locomotion of older rats. NPA-stimulated GTPγS binding was elevated in EEDQ-treated preweanling rats, relative to adults, indicating enhanced functional coupling between the G protein and receptor. EEDQ also reduced ARRB2 levels in all age groups, which is indicative of increased D2 receptor sensitivity. In sum, the present results support the hypothesis that D2 receptor supersensitivity is a critical factor mediating the locomotor potentiating effects of EEDQ in cocaine-treated preweanling rats.
N-乙氧羰基-2-乙氧基-1,2-二氢喹啉（EEDQ）不可逆地使多巴胺（DA）受体失活，导致大鼠出现明显的年龄依赖性行为效应。例如，EEDQ 增强或不影响新生大鼠 DA 激动剂诱导的运动活动，同时减弱青少年和成年大鼠的运动活动。本研究的两个目的是确定 EEDQ 是否会：（a）增强或减弱新生、青少年和成年大鼠可卡因诱导的运动活动；（b）改变存活 D2 受体的敏感性。大鼠在出生后第 17 天（PD）17、第 39 天（PD）39 和第 84 天（PD）84 接受载体或 EEDQ（2.5 或 7.5mg/kg）处理。在行为实验中，24 小时后评估盐水或可卡因诱导的运动活动。在生化实验中，在载体或 EEDQ 处理后 24 小时采集背侧纹状体样本，然后测定 NPA 刺激的 GTPγS 受体结合、G 蛋白偶联受体激酶 6（GRK6）和β-arrestin-2（ARRB2）。GTPγS 结合是配体诱导 G 蛋白激活的直接测量，而 GRK6 和 ARRB2 调节 D2 受体的内化和脱敏。结果表明，EEDQ 增强了新生大鼠的运动活动，而减弱了老年大鼠的运动活动。与成年大鼠相比，EEDQ 处理的新生大鼠 NPA 刺激的 GTPγS 结合增加，表明 G 蛋白与受体之间的功能偶联增强。EEDQ 还降低了所有年龄组的 ARRB2 水平，表明 D2 受体敏感性增加。总之，本研究结果支持 D2 受体超敏性是 EEDQ 增强可卡因处理的新生大鼠运动活动的关键因素的假说。
