可卡因诱导的松鼠猴觅药行为复燃的衰减：κ 阿片受体和 5-羟色胺能机制。
Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys: kappa opioid and serotonergic mechanisms.
机构信息
New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772-9102, USA.
出版信息
Psychopharmacology (Berl). 2010 Jun;210(2):169-77. doi: 10.1007/s00213-009-1705-2. Epub 2009 Oct 27.
RATIONALE
Kappa agonists can attenuate reinstatement of cocaine-seeking behavior induced by cocaine priming. The mechanisms underlying this effect have not been characterized fully but may have a serotonergic component as kappa agonists also increase the release of serotonin (5-hydroxytryptamine, 5-HT).
OBJECTIVES
This study investigated the role of kappa opioid receptor and 5-HT mechanisms in kappa agonist-induced attenuation of cocaine priming in monkeys.
METHODS
Squirrel monkeys were trained to self-administer cocaine (0.18-0.3 mg/kg/injection) under a second-order schedule in which drug seeking was maintained jointly by cocaine injections and a cocaine-paired visual stimulus. In extinction sessions, saline was substituted for cocaine, and the cocaine-paired stimulus was omitted. During test sessions, only saline was available for self-administration, and response-contingent presentations of the cocaine-paired stimulus were restored.
RESULTS
Priming injections of cocaine (0.1-1.0 mg/kg) induced reinstatement of drug seeking. Maximal levels of responding were similar to those maintained by active cocaine self-administration. Pretreatment with the kappa agonists enadoline (0.01 mg/kg) and spiradoline (0.3 mg/kg) or the 5-HT transport inhibitors fluoxetine (5.6 mg/kg) and citalopram (10.0 mg/kg) attenuated the priming effects of cocaine, shifting the cocaine dose-response function rightward and downward. Inhibition of cocaine-induced reinstatement of drug seeking by spiradoline and fluoxetine was reversed by R(+)8-hydroxy-2-(di-n-propylamino)tetralin (0.03 mg/kg), a 5HT(1A) agonist that inhibits 5-HT release. The effects of spiradoline also were reversed by the kappa antagonist nor-binaltorphimine (10.0 mg/kg).
CONCLUSIONS
Results suggest that the capacity of kappa opioid agonists to increase extracellular 5-HT levels may at least partially underlie kappa agonist-induced modulation of cocaine seeking.
原理
κ 阿片受体激动剂可减弱可卡因引发的觅药行为复燃。虽然这种作用的机制尚未完全阐明，但可能具有 5-羟色胺能成分，因为 κ 阿片受体激动剂也会增加 5-羟色胺（5-羟色胺，5-HT）的释放。
目的
本研究旨在探讨 κ 阿片受体和 5-HT 机制在 κ 阿片受体激动剂减弱猴子可卡因引发的觅药行为中的作用。
方法
训练松鼠猴进行可卡因（0.18-0.3mg/kg/注射）的自我给药，采用二阶时间表，其中药物寻求由可卡因注射和可卡因配对的视觉刺激共同维持。在消光期间，用生理盐水代替可卡因，并省略可卡因配对的刺激。在测试期间，仅提供生理盐水用于自我给药，并恢复与可卡因配对的刺激的反应相关呈现。
结果
可卡因（0.1-1.0mg/kg）的引发注射诱导了药物寻求的复燃。最大反应水平与主动可卡因自我给药维持的水平相似。κ 激动剂恩丹醇（0.01mg/kg）和螺旋多醇（0.3mg/kg）或 5-HT 转运抑制剂氟西汀（5.6mg/kg）和西酞普兰（10.0mg/kg）预处理减弱了可卡因的引发作用，使可卡因剂量反应函数向右和向下移动。螺旋多醇和氟西汀抑制可卡因诱导的觅药行为复燃的作用被 5-HT1A 激动剂 R(+)8-羟基-2-（二正丙基氨基）四氢萘（0.03mg/kg）逆转，该激动剂抑制 5-HT 释放。螺旋多醇的作用也被 κ 拮抗剂诺布纳托辛（10.0mg/kg）逆转。
结论
结果表明，κ 阿片受体激动剂增加细胞外 5-HT 水平的能力至少部分解释了 κ 阿片受体激动剂对可卡因寻求的调节作用。
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