Behavioral Neuroscience Branch, IRP/NIDA/NIH, 251 Bayview Blvd, Suite 200, Baltimore, MD, USA.
Eur J Neurosci. 2019 Aug;50(3):2075-2085. doi: 10.1111/ejn.13955. Epub 2018 Aug 1.
Relapse to non-medical use of prescription opioids often occurs after exposure to places previously associated with drug use. Here, we describe a rat model of context-induced reinstatement of oxycodone seeking after repeated cycles of drug self-administration and extinction-induced abstinence. We also determined the role of mu, delta and kappa opioid receptors (MOR, DOR, KOR) in this reinstatement. We trained rats to self-administer oxycodone for 6 h/day in context A; lever pressing was paired with a discrete cue. Next, we extinguished the lever pressing in the presence of the discrete cue in context B and then tested the rats for reinstatement of oxycodone seeking in both contexts. We retrained rats to self-administer oxycodone in context A, re-extinguished their lever pressing in context B and retested them for reinstatement in both contexts. Prior to testing, we injected the rats with vehicle or antagonists of MOR (naltrexone; 0.5 or 1.0 mg/kg), DOR (naltrindole; 7.5 or 15 mg/kg) or KOR (LY2456302; 5 or 10 mg/kg). We also tested the effect of naltrexone, naltrindole and LY2456302 on oxycodone self-administration under fixed-ratio-1 (FR1) and progressive ratio (PR) reinforcement schedules. We observed context-induced reinstatement of oxycodone seeking after repeated cycles of drug self-administration and extinction. Naltrexone, but not naltrindole or LY2456302, injections decreased this reinstatement. Additionally, naltrexone increased oxycodone self-administration under the FR1 schedule and decreased oxycodone self-administration under the PR schedule; naltrindole and LY2456302 were ineffective. Results demonstrate a critical role of MOR, but not DOR or KOR, in context-induced reinstatement of oxycodone seeking and oxycodone self-administration.
在接触以前与药物使用相关的环境后，经常会发生非医疗用途处方阿片类药物的复吸。在这里，我们描述了一个在反复药物自我给药和戒断诱导的禁欲后，通过环境线索诱导阿片类药物觅药行为复吸的大鼠模型。我们还确定了 μ、δ 和 κ 阿片受体（MOR、DOR、KOR）在这种复吸中的作用。我们训练大鼠在环境 A 中每天自我注射阿片类药物 6 小时；按压杠杆与离散线索配对。接下来，我们在环境 B 中存在离散线索的情况下消除按压杠杆，然后在两个环境中测试大鼠对阿片类药物觅药行为的复吸。我们重新训练大鼠在环境 A 中自我注射阿片类药物，在环境 B 中重新消除按压杠杆，并在两个环境中重新测试它们的复吸。在测试之前，我们给大鼠注射载体或 MOR（纳曲酮；0.5 或 1.0mg/kg）、DOR（naltrindole；7.5 或 15mg/kg）或 KOR（LY2456302；5 或 10mg/kg）拮抗剂。我们还测试了纳曲酮、naltrindole 和 LY2456302 对固定比率-1（FR1）和递增比率（PR）强化方案下阿片类药物自我给药的影响。我们观察到在反复的药物自我给药和戒断后，环境线索会引发阿片类药物觅药行为的复吸。纳曲酮而非 naltrindole 或 LY2456302 注射可减少这种复吸。此外，纳曲酮增加了 FR1 方案下的阿片类药物自我给药，降低了 PR 方案下的阿片类药物自我给药；naltrindole 和 LY2456302 则无效。结果表明，MOR 而非 DOR 或 KOR 在环境线索诱导的阿片类药物觅药行为复吸和阿片类药物自我给药中起关键作用。
