Lee Buyean, Tiefenbacher Stefan, Platt Donna M, Spealman Roger D
Harvard Medical School, New England Primate Research Center, Southborough, MA 01772-9102, USA.
Neuropsychopharmacology. 2004 Apr;29(4):686-93. doi: 10.1038/sj.npp.1300391.
Converging evidence suggests a role for noradrenergic mechanisms in stress-induced reinstatement of cocaine seeking in animals. Yohimbine, an alpha(2)-adrenoceptor antagonist, is known to be anxiogenic and induce stress-related responses in humans and animals. Here, we tested the ability of yohimbine to reinstate cocaine-seeking behavior and induce behavioral and physiological signs characteristic of stress in squirrel monkeys. Monkeys were trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Drug seeking subsequently was extinguished by substituting saline for cocaine injections and omitting the cocaine-paired stimulus. The ability of yohimbine and the structurally distinct alpha(2)-adrenoceptor antagonist RS-79948 to reinstate cocaine-seeking behavior was assessed by administering priming injections immediately before test sessions in which the cocaine-paired stimulus was either present or absent. Priming injections of yohimbine (0.1-0.56 mg/kg, i.m.) or RS-79948 (0.01-0.1 mg/kg, i.m.) induced dose-related reinstatement of cocaine-seeking behavior. The magnitude of yohimbine-induced reinstatement was similar regardless of the presence or absence of the cocaine-paired stimulus. Yohimbine also significantly increased salivary cortisol levels, a physiological marker of stress, as well as scratching and self-grooming, behavioral markers of stress in nonhuman primates. In drug interaction experiments, pretreatment with the alpha(2)-adrenoceptor agonist clonidine (0.1-0.3 mg/kg, i.m.) dose-dependently inhibited yohimbine-induced reinstatement of cocaine seeking. In contrast, pretreatment with the dopamine receptor antagonist flupenthixol failed to inhibit yohimbine-induced reinstatement of cocaine seeking. The results show that pharmacological blockade of alpha(2)-adrenoceptors can induce reinstatement of cocaine-seeking behavior and characteristic stress responses in squirrel monkeys, providing a potentially useful model of stress-induced relapse to drug seeking.
越来越多的证据表明，去甲肾上腺素能机制在动物应激诱导的可卡因觅求恢复中起作用。育亨宾是一种α(2)-肾上腺素能受体拮抗剂，已知它具有致焦虑作用，并能在人类和动物中诱发与应激相关的反应。在此，我们测试了育亨宾恢复松鼠猴可卡因觅求行为以及诱发应激特征性行为和生理体征的能力。猴子在静脉注射药物的二级程序下接受训练以自我给药可卡因。随后通过用生理盐水替代可卡因注射并省略与可卡因配对的刺激来消除药物觅求行为。通过在测试时段前立即给予启动注射来评估育亨宾和结构不同的α(2)-肾上腺素能受体拮抗剂RS-79948恢复可卡因觅求行为的能力，测试时段中可卡因配对刺激存在或不存在。育亨宾（0.1 - 0.56毫克/千克，肌肉注射）或RS-79948（0.01 - 0.1毫克/千克，肌肉注射）的启动注射诱导了与剂量相关的可卡因觅求行为恢复。无论可卡因配对刺激存在与否，育亨宾诱导的恢复程度相似。育亨宾还显著提高了唾液皮质醇水平，这是应激的生理标志物，以及抓挠和自我梳理行为，这是非人类灵长类动物应激的行为标志物。在药物相互作用实验中，用α(2)-肾上腺素能受体激动剂可乐定（0.1 - 0.3毫克/千克，肌肉注射）预处理剂量依赖性地抑制了育亨宾诱导的可卡因觅求恢复。相反，用多巴胺受体拮抗剂氟哌噻吨预处理未能抑制育亨宾诱导的可卡因觅求恢复。结果表明，α(2)-肾上腺素能受体的药理学阻断可诱导松鼠猴可卡因觅求行为的恢复和特征性应激反应，为应激诱导的药物觅求复发提供了一个潜在有用的模型。
