Zapata Agustin, Shippenberg Toni S
Integrative Neuroscience Section, Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland 21224, USA.
Alcohol Clin Exp Res. 2006 Apr;30(4):592-7. doi: 10.1111/j.1530-0277.2006.00069.x.
Endogenous kappa-opioid receptor (KOPR) systems modulate the actions of several drugs of abuse. Their role in modulating the effects of ethanol is unknown. An increase in nucleus accumbens extracellular dopamine (DA) has been implicated in mediating the rewarding and locomotor-activating effects of ethanol and virtually all drugs of abuse. The present microdialysis studies were conducted to determine whether the lack of KOPR alters ethanol-evoked DA levels in the nucleus accumbens of naïve mice and whether a similar effect is observed in mice repeatedly exposed to ethanol.
Gene deletion techniques were used in conjunction with in vivo microdialysis to examine the influence of lack of KOPR on ethanol-evoked DA in the nucleus accumbens. To determine whether pharmacological inactivation of KOPR produces similar effects in naïve mice and those repeatedly exposed to ethanol, the KOPR antagonist norbinaltorphimine (n-BNI) was administered in wild-type mice before repeated air or ethanol vapor inhalation. Microdialysis was conducted 24 hours later.
Acute ethanol administration increased DA levels in the nucleus accumbens of wild-type mice. In littermates lacking the KOPR gene, ethanol-evoked DA levels were enhanced. Prior ethanol exposure reduced ethanol-evoked DA levels in vehicle-treated and n-BNI-treated mice. Statistical analysis, however, revealed a significant main effect of n-BNI, indicating that KOPR blockade increased ethanol-evoked DA levels in naïve mice and repeated ethanol exposure attenuated, but did not abolish, this effect.
These findings demonstrate that inhibition of KOPR leads to increased sensitivity to the DA-releasing effects of ethanol in the nucleus accumbens.
内源性κ-阿片受体（KOPR）系统调节多种滥用药物的作用。其在调节乙醇作用方面的作用尚不清楚。伏隔核细胞外多巴胺（DA）的增加与介导乙醇以及几乎所有滥用药物的奖赏和运动激活作用有关。本微透析研究旨在确定KOPR的缺失是否会改变未接触过乙醇的小鼠伏隔核中乙醇诱发的DA水平，以及在反复接触乙醇的小鼠中是否会观察到类似的效应。
基因缺失技术与体内微透析相结合，以研究KOPR缺失对伏隔核中乙醇诱发的DA的影响。为了确定KOPR的药理学失活在未接触过乙醇的小鼠和反复接触乙醇的小鼠中是否产生类似的效应，在野生型小鼠反复吸入空气或乙醇蒸气之前，给予KOPR拮抗剂纳洛酮啡（n-BNI）。24小时后进行微透析。
急性给予乙醇可增加野生型小鼠伏隔核中的DA水平。在缺乏KOPR基因的同窝小鼠中，乙醇诱发的DA水平升高。先前接触乙醇可降低溶剂处理组和n-BNI处理组小鼠中乙醇诱发的DA水平。然而，统计分析显示n-BNI有显著的主效应，表明KOPR阻断增加了未接触过乙醇的小鼠中乙醇诱发的DA水平，反复接触乙醇可减弱但并未消除这种效应。
这些发现表明，抑制KOPR会导致伏隔核对乙醇释放DA的作用敏感性增加。
