PG01037，一种新型的多巴胺 D3 受体拮抗剂，可抑制 methamphetamine 在大鼠体内的作用。
PG01037, a novel dopamine D3 receptor antagonist, inhibits the effects of methamphetamine in rats.
机构信息
Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institute of Health, Biomedical Research Center, 251 Bayview Boulevard, Baltimore, MD 21224 USA.
出版信息
J Psychopharmacol. 2011 Feb;25(2):263-73. doi: 10.1177/0269881109358201. Epub 2010 Feb 8.
Our previous studies have shown that the selective dopamine D(3) receptor antagonists SB-277011A or NGB 2904 significantly attenuate cocaine self-administration under a progressive-ratio reinforcement schedule and cocaine-, methamphetamine- or nicotine-enhanced brain stimulation reward. However, the poor bioavailability of SB-277011A has limited its potential use in humans. In the present study, we investigated the effects of the novel D(3) receptor antagonist PG01037 on methamphetamine self-administration, methamphetamine-associated cue-induced reinstatement of drug seeking and methamphetamine-enhanced brain stimulation reward. Rats were allowed to intravenously self-administer methamphetamine under fixed-ratio 2 and progressive-ratio reinforcement conditions, and then the effects of PG01037 on methamphetamine self-administration and cue-induced reinstatement were assessed. Additional groups of rats were trained for intracranial electrical brain stimulation reward and the effects of PG01037 and methamphetamine on brain stimulation reward were assessed. Acute intraperitoneal administration of PG01037 (3, 10, 30 mg/kg) failed to alter methamphetamine or sucrose self-administration under fixed-ratio 2 reinforcement, but significantly lowered the break-point levels for methamphetamine or sucrose self-administration under progressive-ratio reinforcement. In addition, PG01037 significantly inhibited methamphetamine-associated cue-triggered reinstatement of drug-seeking behavior and methamphetamine-enhanced brain stimulation reward. These data suggest that the novel D(3) antagonist PG01037 significantly attenuates the rewarding effects as assessed by progressive-ratio self-administration and brain stimulation reward, and inhibits methamphetamine-associated cue-induced reinstatement of drug-seeking behavior These findings support the potential use of PG01037 or other selective D(3) antagonists in the treatment of methamphetamine addiction.
我们之前的研究表明，选择性多巴胺 D(3)受体拮抗剂 SB-277011A 或 NGB 2904 可显著减弱可卡因在递增比率强化方案下的自我给药，以及可卡因、甲基苯丙胺或尼古丁增强的脑刺激奖赏。然而，SB-277011A 的生物利用度差限制了其在人类中的潜在用途。在本研究中，我们研究了新型 D(3)受体拮抗剂 PG01037 对甲基苯丙胺自我给药、甲基苯丙胺相关线索诱发的觅药行为复吸以及甲基苯丙胺增强的脑刺激奖赏的影响。大鼠被允许静脉内自我给予甲基苯丙胺，采用固定比率 2 和递增比率强化条件，然后评估 PG01037 对甲基苯丙胺自我给药和线索诱发复吸的影响。另外一组大鼠接受了颅内电脑刺激奖赏的训练，评估了 PG01037 和甲基苯丙胺对脑刺激奖赏的影响。急性腹腔内给予 PG01037（3、10、30mg/kg）未能改变固定比率 2 强化下的甲基苯丙胺或蔗糖自我给药，但显著降低了递增比率强化下的甲基苯丙胺或蔗糖自我给药的断点水平。此外，PG01037 显著抑制了甲基苯丙胺相关线索诱发的觅药行为复吸和甲基苯丙胺增强的脑刺激奖赏。这些数据表明，新型 D(3)拮抗剂 PG01037 显著减弱了递增比率自我给药和脑刺激奖赏评估的奖赏效应，并抑制了甲基苯丙胺相关线索诱发的觅药行为复吸。这些发现支持 PG01037 或其他选择性 D(3)拮抗剂在治疗甲基苯丙胺成瘾中的潜在用途。
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