Soderman Avery R, Unterwald Ellen M
Department of Pharmacology, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Brain Res. 2009 Nov 3;1296:63-71. doi: 10.1016/j.brainres.2009.08.035. Epub 2009 Aug 20.
Previous studies by our laboratory have demonstrated that the mu opioid receptor antagonist, CTAP, blocks the rewarding effects of cocaine when it is injected directly into the nucleus accumbens or ventral tegmental area (VTA). This finding suggests that cocaine is causing the release of endogenous opioid peptides which activate mu opioid receptors within the nucleus accumbens and VTA. The purpose of the present study was to characterize the dose-response and time-course of mu receptor occupancy following systemic cocaine administration and to determine if release of endogenous opioids by cocaine is mediated by activation of D1 or D2 dopamine receptors. Quantitative in vitro receptor autoradiography was used to measure the regional displacement of (3)H-DAMGO binding following cocaine administration. Adult male Sprague-Dawley rats were given intraperitoneal (i.p.) injections of cocaine and their brains were removed at various times and prepared for mu opioid receptor quantitation. To determine the role of dopamine D1 and D2 receptors in the effect of cocaine on mu receptor occupancy, rats were injected with the selective D1 or D2 receptor antagonists SCH23390 or eticlopride prior to cocaine. For all studies, (3)H-DAMGO binding to mu opioid receptors was measured in the nucleus accumbens, caudate putamen, frontal cortex, olfactory tubercle and VTA. Results demonstrate that cocaine administration caused a time- and dose-dependent reduction in (3)H-DAMGO binding within the nucleus accumbens core and shell. The reduction in mu receptor binding was attenuated by pretreatment with eticlopride. These results suggest that cocaine, acting via D2 dopamine receptors, can cause the release of an endogenous opioid peptide that binds to mu opioid receptors within the nucleus accumbens.
我们实验室之前的研究表明，μ阿片受体拮抗剂CTAP直接注射到伏隔核或腹侧被盖区（VTA）时，可阻断可卡因的奖赏效应。这一发现表明，可卡因会导致内源性阿片肽释放，从而激活伏隔核和VTA内的μ阿片受体。本研究的目的是确定全身给予可卡因后μ受体占有率的剂量反应和时间进程，并确定可卡因引起的内源性阿片类物质释放是否由D1或D2多巴胺受体的激活介导。采用定量体外受体放射自显影术测量可卡因给药后（3）H-DAMGO结合的区域位移。成年雄性Sprague-Dawley大鼠腹腔注射可卡因，并在不同时间取出大脑，准备进行μ阿片受体定量分析。为了确定多巴胺D1和D2受体在可卡因对μ受体占有率影响中的作用，在给予可卡因之前，给大鼠注射选择性D1或D2受体拮抗剂SCH23390或艾替洛尔。在所有研究中，均在伏隔核、尾状壳核、额叶皮质、嗅结节和VTA中测量（3）H-DAMGO与μ阿片受体的结合。结果表明，可卡因给药导致伏隔核核心和壳层内（3）H-DAMGO结合呈时间和剂量依赖性减少。用艾替洛尔预处理可减弱μ受体结合的减少。这些结果表明，可卡因通过D2多巴胺受体发挥作用，可导致内源性阿片肽释放，该肽与伏隔核内的μ阿片受体结合。
