"Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats".
"Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats".
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DOI：
10.1007/s00213-017-4647-0
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发表时间：
2017-08
影响因子：
3.4
通讯作者：
Kreek MJ
中科院分区：
文献类型：
--
作者：
Valenza M;Butelman ER;Kreek MJ
压力回路的招募有助于从积极到消极的强化机制的转变，维持长期的可卡因成瘾。κ阿片受体（KOPr）信号转导通过应激和慢性可卡因暴露而上调。虽然KOPr激动剂诱导快感缺乏和烦躁不安，但KOPr拮抗剂显示抗抑郁和抗焦虑特性。大多数关于KOPr拮抗作用的知识是基于具有不寻常的药代动力学和药效学特性的药物，使结果的解释复杂化。在这里，我们的特点是在体内的行为和神经内分泌作用的新的相对短效KOPr拮抗剂LY 2444296。到目前为止，没有研究调查是否系统性KOPr阻断减少焦虑样和抑郁样行为的动物先前暴露于慢性延长获取可卡因自我管理。我们测试了LY 2444296在阻断KOPr介导的厌恶和神经内分泌作用中的作用。然后，我们测试了急性全身性LY 2444296在减少焦虑和抑郁样行为以及释放应激激素皮质酮（CORT）方面的作用，这是在慢性延长接触（18小时/天，持续14天）可卡因自我给药后观察到的。LY 2444296阻断了U69，593诱导的位置厌恶和减少的运动活动，以及U69，593诱导的血清CORT释放，这证实了其主要作用部位，本身没有发挥作用。LY 2444296的急性全身给药减少了慢性延长使用可卡因自我给药后测试的大鼠中的焦虑样和抑郁样行为以及CORT释放，但在可卡因初治大鼠中没有。结果表明，急性封锁KOPr的相对短效拮抗剂产生治疗样的影响，选择性地在大鼠慢性扩展访问可卡因自我管理的历史。
The recruitment of the stress circuitry contributes to a shift from positive to negative reinforcement mechanisms sustaining long-term cocaine addiction. The kappa opioid receptor (KOPr) signaling is upregulated by stress and chronic cocaine exposure. While KOPr agonists induce anhedonia and dysphoria, KOPr antagonists display antidepressant and anxiolytic properties. Most of the knowledge on KOPr antagonism is based on drugs with unusual pharmacokinetic and pharmacodynamic properties, complicating interpretation of results. Here we characterized in vivo behavioral and neuroendocrine effects of the novel relatively short-acting KOPr antagonist LY2444296. To date, no study has investigated whether systemic KOPr blockade reduced anxiety-like and depressive-like behaviors in animals previously exposed to chronic extended access cocaine self-administration. We tested the effect of LY2444296 in blocking KOPr-mediated aversive and neuroendocrine effects. Then, we tested acute systemic LY2444296 in reducing anxiety- and depression-like behaviors, as well as releasing the stress hormone corticosterone (CORT), observed after chronic extended access (18 h/day for 14 days) cocaine self-administration. LY2444296 blocked both U69,593-induced place aversion and reduced motor activity, as well as U69,593-induced release of serum CORT, which confirmed its major site of action, without exerting an effect per se. Acute systemic administration of LY2444296 reduced anxiety-like and depressive-like behaviors, as well as CORT release, in rats tested after chronic extended access cocaine self-administration, but not in cocaine naïve rats. Results suggest that acute blockade of KOPr by a relatively short-acting antagonist produces therapeutic-like effects selectively in rats with a history of chronic extended access cocaine self-administration.
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影响因子：
2.5
作者：
Huang P;Yakovleva T;Aldrich JV;Tunis J;Parry C;Liu-Chen LY
通讯作者：
Liu-Chen LY
影响因子：
7.4
作者：
Carlezon WA Jr;Krystal AD
通讯作者：
Krystal AD
影响因子：
4.8
作者：
Elda Maqueda, Ana;Valle, Marta;Riba, Jordi
通讯作者：
Riba, Jordi
影响因子：
3.4
作者：
Fagergren, P;Smith, HR;Hurd, YL
通讯作者：
Hurd, YL
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.