Schank Jesse R, Liles L Cameron, Weinshenker David
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Biol Psychiatry. 2008 Jun 1;63(11):1007-12. doi: 10.1016/j.biopsych.2007.10.018. Epub 2008 Feb 20.
Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety.
In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety.
We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/-) mice, as measured by a decrease in open arm exploration. The Dbh -/- mice had normal baseline performance in the EPM but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/- mice following administration of disulfiram, a dopamine beta-hydroxylase (DBH) inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the beta-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/- and wild-type C57BL6/J mice, while the alpha(1) antagonist prazosin and the alpha(2) antagonist yohimbine had no effect.
These results indicate that noradrenergic signaling via beta-adrenergic receptors is required for cocaine-induced anxiety in mice.
可卡因是一种广泛滥用的精神兴奋剂，具有奖赏和厌恶两种特性。虽然对可卡因奖赏效应的潜在机制已进行了广泛研究，但对可卡因诱发的不愉快行为状态（如焦虑）的关注较少。
在本研究中，我们评估了缺乏去甲肾上腺素（NE）的多巴胺β-羟化酶基因敲除（Dbh-/-）小鼠在高架十字迷宫（EPM）中的行为表现，以研究去甲肾上腺素能信号传导对可卡因诱发焦虑的作用。
我们发现，可卡因能剂量依赖性地增加对照（Dbh+/-）小鼠的焦虑样行为，这通过开放臂探索次数减少来衡量。Dbh-/-小鼠在EPM中的基线表现正常，但对可卡因的致焦虑作用完全有抗性。在给予双硫仑（一种多巴胺β-羟化酶（DBH）抑制剂）后，Dbh+/-小鼠中可卡因诱发的焦虑也有所减轻。在使用特定肾上腺素能拮抗剂进行的实验中，我们发现用β-肾上腺素能受体拮抗剂普萘洛尔预处理可阻断Dbh+/-和野生型C57BL6/J小鼠中可卡因诱发的焦虑样行为，而α（1）拮抗剂哌唑嗪和α（2）拮抗剂育亨宾则无此作用。
这些结果表明，通过β-肾上腺素能受体的去甲肾上腺素能信号传导是小鼠中可卡因诱发焦虑所必需的。
