Gatch Michael B, Jung Marianna E, Wallis Cleatus J, Lal Harbans
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth 76107-2699, USA.
Life Sci. 2002 Oct 18;71(22):2657-65. doi: 10.1016/s0024-3205(02)02111-2.
Male Long-Evans rats were trained to discriminate mCPP (1.4 mg/kg, i.p.) from saline, using a two-lever, food-reinforced operant task. The GABA(A) antagonist, bicuculline (0.16-0.64 mg/kg), partially substituted for mCPP, whereas the benzodiazepine antagonist, flumazenil (1-10 mg/kg), and the benzodiazepine inverse agonist, Ro 15-4513 (0.25-2.5 mg/kg), failed to substitute for mCPP. Bicuculline produced no change in response rate, whereas Ro 15-4513 dose-dependently decreased responding. Flumazenil produced a small increase in response rates. Flumazenil (10 mg/kg), Ro 15-4513 (1.25 mg/kg), and the benzodiazepine agonists alprazolam (0.64 mg/kg) and diazepam (5 mg/kg) full agonist all failed to block the mCPP discriminative stimulus. When given in combination with mCPP, Ro15-4513 and alprazolam both produced lower response rates than did mCPP alone, whereas flumazenil and diazepam did not significantly alter response rates. These findings provide evidence that GABA(A) antagonists modulate the discriminative stimulus effects of mCPP, but that these effects are not mediated by activity at the benzodiazepine site.
雄性Long-Evans大鼠接受训练，通过双杠杆食物强化操作性任务来区分腹腔注射1.4毫克/千克的mCPP和生理盐水。GABA(A)拮抗剂荷包牡丹碱（0.16 - 0.64毫克/千克）部分替代了mCPP，而苯二氮䓬拮抗剂氟马西尼（1 - 10毫克/千克）和苯二氮䓬反向激动剂Ro 15 - 4513（0.25 - 2.5毫克/千克）未能替代mCPP。荷包牡丹碱对反应率没有影响，而Ro 15 - 4513剂量依赖性地降低反应。氟马西尼使反应率略有增加。氟马西尼（10毫克/千克）、Ro 15 - 4513（1.25毫克/千克）以及苯二氮䓬激动剂阿普唑仑（0.64毫克/千克）和地西泮（5毫克/千克）全激动剂均未能阻断mCPP的辨别性刺激。当与mCPP联合使用时，Ro15 - 4513和阿普唑仑产生的反应率均低于单独使用mCPP时，而氟马西尼和地西泮并未显著改变反应率。这些发现提供了证据，表明GABA(A)拮抗剂调节mCPP的辨别性刺激作用，但这些作用不是由苯二氮䓬位点的活性介导的。
