Effects of kappa opioids on cocaine self-administration by rhesus monkeys.
Effects of kappa opioids on cocaine self-administration by rhesus monkeys.
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发表时间：
1997-07
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通讯作者：
S. Negus;N. Mello;P. Portoghese;Chai En Lin
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作者：
S. Negus;N. Mello;P. Portoghese;Chai En Lin
Kappa阿片类激动剂可减弱可卡因的某些神经化学和行为影响，被认为是治疗可卡因依赖的潜在方法。本研究检测了两种阿片受体激动剂苯佐莫芬乙基酮环唑辛（EKC）和芳基乙酰胺U50,488对恒河猴可卡因自我给药的影响。在每天交替的可卡因和食物供应期间，猴子对0.032毫克/公斤可卡因注射（静脉注射）和1克香蕉味食物颗粒有反应。连续10天使用EKC （0.0032-0.032 mg/kg/hr）或U50,488 （0.032-0.1 mg/kg/hr）慢性治疗可在可卡因剂量-效应曲线峰值处（0.01和0.032 mg/kg/注射）减少单位剂量的可卡因自我给药。在10天的治疗过程中，可卡因自我给药的减少常常持续。减少可卡因自我给药的EKC和U50,488的剂量通常也会减少维持食物的反应。此外，EKC和U50,488在治疗的最初几天经常产生呕吐和镇静作用，尽管对这些作用的耐受性似乎迅速发展。一般来说，在减少可卡因自我给药的剂量下，EKC比U50,488产生更少的不良影响。卡帕拮抗剂去甲萘多啡胺（3.2 mg/kg）不影响可卡因或食物维持的反应。然而，去甲萘哌胺（3.2 mg/kg）和阿片拮抗剂纳洛酮（1.0 mg/kg/hr）均阻断了EKC和U50,488的作用。这些结果表明，长期给药EKC和U50,588产生剂量依赖性，kappa受体介导，并且经常持续减少可卡因自我给药。然而，这些卡帕激动剂也会产生不良的行为影响，这可能会使它们作为可卡因依赖治疗的使用复杂化。
Kappa opioid agonists attenuate some neurochemical and behavioral effects of cocaine and are being considered as potential treatments for cocaine dependence. The present study examined the effects of two kappa opioid agonists, the benzomorphan ethylketocyclazocine (EKC) and the arylacetamide U50,488, on cocaine self-administration in rhesus monkeys. Monkeys responded for 0.032 mg/kg/injection cocaine (i.v.) and 1 g banana-flavored food pellets during alternating daily sessions of cocaine and food availability. Chronic treatment for 10 consecutive days with EKC (0.0032-0.032 mg/kg/hr) or U50,488 (0.032-0.1 mg/kg/hr) dose-dependently decreased self-administration of cocaine unit doses at the peak of the cocaine dose-effect curve (0.01 and 0.032 mg/kg/injection). These decreases in cocaine self-administration were often sustained throughout the 10 days of treatment. Doses of EKC and U50,488 that decreased cocaine self-administration usually decreased food-maintained responding as well. In addition, EKC and U50,488 often produced emesis and sedation during the first few days of treatment, although tolerance appeared to develop rapidly to these effects. In general, EKC produced fewer undesirable effects than U50,488 at doses that decreased cocaine self-administration. The kappa antagonist norbinaltorphimine (3.2 mg/kg) did not affect responding maintained by cocaine or food. However, both norbinaltorphimine (3.2 mg/kg) and the opioid antagonist naloxone (1.0 mg/kg/hr) blocked the effects of EKC and U50,488. These results indicate that chronic administration of EKC and U50,588 produce a dose-dependent, kappa receptor-mediated and often sustained decrease in cocaine self-administration. However, these kappa agonists also produce undesirable behavioral effects that may complicate their use as treatments for cocaine dependence.