Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats.
Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats.
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DOI：
10.1016/j.neuropharm.2011.06.014
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发表时间：
2012-01
影响因子：
4.7
通讯作者：
Carlezon, William A.
中科院分区：
文献类型：
--
作者：
Chartoff, Elena;Sawyer, Allison;Rachlin, Anna;Potter, Dave;Pliakas, Andrea;Carlezon, William A.
药物依赖的特征是大脑奖赏系统失调和对压力的敏感性增加。长期暴露于滥用药物与神经肽强啡肽（κ阿片受体（KOR）的内源性配体）的表达增加有关。KOR的激活导致啮齿类动物的抑郁和厌恶样反应，提高了药物诱导的强啡肽上调在独立相关的消极状态中发挥作用的可能性。在这里，我们使用“狂欢”暴露于可卡因（每天3次腹腔注射15 mg/kg，持续14天），以检查颅内自我刺激（ICSS）试验和强迫游泳试验（FST）中依赖样行为的发展。当大鼠在每天第一次预定注射前立即进行测试时-停药期对应于前一天最后一次注射后20小时-ICSS阈值（一种假定的快感缺乏指标）呈依赖性增加，FST（一种假定的行为绝望指标）中的Lavenity至不动性降低。在ICSS试验中，在狂欢方案开始前给予长效KOR拮抗剂norBNI（20 μg，脑室内）可减轻可卡因戒断诱导的快感缺失的发生。相比之下，norBNI的管理中的狂欢方案没有影响可卡因戒断诱导快感缺失的表达在ICSS测试，虽然它确实减弱绝望样行为在FST。这些数据表明，在暴露于压力源（在这种情况下，可卡因戒断或强迫游泳）之前阻断KOR可以减弱压力诱导的行为适应的发展。
Drug dependence is characterized bydysregulation of brain reward systems and increased sensitivity to stress. Chronic exposure to drugs of abuse is associated with increased expression of the neuropeptide dynorphin, the endogenous ligand for kappa opioid receptors (KORs). Activation of KORs causes depressive- and aversive-like responses in rodents, raising the possibility that drug-induced upregulation of dynorphinplays a role independence-associated negative states. Here we used “binge” exposure to cocaine (3 daily intraperitoneal injections of 15 mg/kg for 14 days) to examine the development of dependence-like behavior in the intracranial self-stimulation (ICSS) test and the forced swim test (FST). When rats were tested immediately before their first scheduled injection of each day—a period of drug withdrawal corresponding to 20 hr after their last injection on the previous day—there were exposure-dependent increases in ICSS thresholds (a putative indicator of anhedonia) and decreases in latencies to immobility in the FST (a putative indicator of behavioral despair). Administration of the long-lasting KOR antagonist norBNI (20 μg, intracerebroventricular) before the beginning of the binge regimen attenuated the development of cocaine withdrawal-induced anhedonia in the ICSS test. In contrast, administration of norBNI in the midst of the binge regimen had no effect on expression of cocaine withdrawal-induced anhedonia in the ICSS test, although it did attenuate despair-like behavior in the FST. These data suggest that blockade of KORs before exposure to a stressor (in this case, cocaine withdrawal or forced swimming) can attenuate the development of stress-induced behavioral adaptations.
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影响因子：
2.9
作者：
Bruchas MR;Land BB;Chavkin C
通讯作者：
Chavkin C
影响因子：
3.4
作者：
BALSKUBIK, R;HERZ, A;SHIPPENBERG, TS
通讯作者：
SHIPPENBERG, TS
影响因子：
14.8
作者：
Carlezon, William A., Jr.;Chartoff, Elena H.
通讯作者：
Chartoff, Elena H.
影响因子：
3.4
作者：
Goussakov, I;Chartoff, EH;Bolshakov, VY
通讯作者：
Bolshakov, VY
DOI：
10.1124/jpet.107.127415
发表时间：
2007-12-01
影响因子：
3.5
作者：
Knoll, Allison T.;Meloni, Edward G.;Carlezon, William A., Jr.
通讯作者：
Carlezon, William A., Jr.