Effects of the kappa-opioid receptor antagonist nor-binaltorphimine on methamphetamine-vs-food choice in male rhesus monkeys

IF 3.9 2区 医学 Q1 PSYCHIATRY
Matthew L. Banks , Kenner C. Rice
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Abstract

Background

Kappa-opioid receptors (KOR) are hypothesized to be involved in mediating ongoing methamphetamine self-administration. Previous rat studies have demonstrated that treatment with the KOR antagonist nor-binaltorphimine (nor-BNI) decreases methamphetamine self-administration. However, KOR antagonist effects on methamphetamine self-administration in nonhuman primates are unknown.

Methods

Operant behavior was maintained under a concurrent schedule of banana-flavored pellets (fixed-ratio 100 schedule) and intravenous methamphetamine injections (0–0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined 7 days before and for up to 28 days following 10 mg/kg, intramuscular nor-BNI treatment.

Results

Under continuous saline treatment conditions, methamphetamine-maintained a dose-dependent increase in choice over the alternative food reinforcer. 10 mg/kg nor-BNI failed to attenuate methamphetamine choice and trended towards increased methamphetamine choice. Methamphetamine choice returned to pre-nor-BNI treatment levels by 21 or 28 days in all 3 monkeys.

Conclusions

The present results do not support the hypothesis that the KOR/dynorphin system robustly modulates methamphetamine self-administration and that KOR antagonists should be considered as methamphetamine use disorder pharmacotherapies. In contrast, these results suggest KOR antagonism may increase methamphetamine reinforcement through blockade of methamphetamine-induced dynorphin release and consequent feedback inhibition.
kappa-阿片受体拮抗剂对雄性恒河猴甲基苯丙胺与食物选择的影响
kappa -阿片受体(KOR)被假设参与调解正在进行的甲基苯丙胺自我给药。先前的大鼠研究表明,用KOR拮抗剂非甲萘哌啶(nor-BNI)治疗可减少甲基苯丙胺的自我给药。然而,KOR拮抗剂对非人类灵长类动物甲基苯丙胺自我给药的影响尚不清楚。方法观察3只雄性恒河猴在香蕉味微丸(固定比例100)和甲基苯丙胺静脉注射(0 ~ 0.32 mg/kg/针,固定比例10)同时注射的情况下的操作行为。测定甲基苯丙胺选择剂量效应函数,在肌注非bni治疗前7天和治疗后28天。结果在持续生理盐水处理条件下,甲基苯丙胺对食物强化剂的选择呈剂量依赖性增加。10 mg/kg非bni不能减少甲基苯丙胺的选择,并有增加甲基苯丙胺选择的趋势。在所有3只猴子中,甲基苯丙胺的选择在21天或28天后恢复到非bni治疗前的水平。结论目前的结果不支持KOR/dynorphin系统强有力地调节甲基苯丙胺自我给药的假设,并且应该将KOR拮抗剂视为甲基苯丙胺使用障碍药物治疗。相反,这些结果表明,KOR拮抗剂可能通过阻断甲基苯丙胺诱导的强啡释放和随后的反馈抑制来增加甲基苯丙胺的强化。
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来源期刊
Drug and alcohol dependence
Drug and alcohol dependence 医学-精神病学
CiteScore
7.40
自引率
7.10%
发文量
409
审稿时长
41 days
期刊介绍: Drug and Alcohol Dependence is an international journal devoted to publishing original research, scholarly reviews, commentaries, and policy analyses in the area of drug, alcohol and tobacco use and dependence. Articles range from studies of the chemistry of substances of abuse, their actions at molecular and cellular sites, in vitro and in vivo investigations of their biochemical, pharmacological and behavioural actions, laboratory-based and clinical research in humans, substance abuse treatment and prevention research, and studies employing methods from epidemiology, sociology, and economics.
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