Brandsgaard R, Barrett J E, Rosenzweig-Lipson S
Wyeth-Ayerst Research, Princeton, New Jersey, USA.
J Pharmacol Exp Ther. 2000 Oct;295(1):382-91.
The discriminative stimulus (DS) effects of 4-aminopyridine (4-AP) were evaluated in 36 male Sprague-Dawley rats that were trained to discriminate 4-AP from saline in a standard two-lever food reinforced drug discrimination procedure. 4-AP along with its structural analogs 3-aminopyridine (3-AP), 2-aminopyridine (2-AP), and 2,3-diaminopyridine (2,3-DIAP) produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever with full substitution at one or more doses. 2,6-Diaminopyridine (2, 6-DIAP) and 3,4-diaminopyridine (3,4-DIAP) produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever but only partially substituted for 4-AP. Neither 4-dimethylaminopyridine (4-DMAP) nor pyridine substituted for 4-AP. Substitution studies were also conducted with indirect dopamine, norepinephrine, serotonin, and acetylcholine agonists, and gamma-aminobutyric acid A (GABA(A)) agonists and antagonists. The norepinephrine reuptake inhibitor tomoxetine, but not nisoxetine or imipramine, produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever and partially substituted for 4-AP. In addition, antagonism studies were conducted using indirect dopamine, norepinephrine, serotonin, acetylcholine antagonists, and GABA(A) agonists as pretreatments to the training dose of 4-AP. The benzodiazepine agonists chlordiazepoxide and diazepam dose dependently attenuated the DS effects of 4-AP. The present results demonstrate that the K-channel blocker 4-AP can be trained as a DS in rats and the DS effects of 4-AP are likely mediated through blockade of voltage-dependent K-channels. The results also demonstrate a novel interaction between benzodiazepines and K-channels.
在36只雄性斯普拉格-道利大鼠中评估了4-氨基吡啶（4-AP）的辨别性刺激（DS）效应。这些大鼠在标准的双杠杆食物强化药物辨别程序中接受训练，以区分4-AP和生理盐水。4-AP及其结构类似物3-氨基吡啶（3-AP）、2-氨基吡啶（2-AP）和2,3-二氨基吡啶（2,3-DIAP）在一个或多个剂量下完全替代时，与4-AP相关杠杆上的反应百分比呈剂量依赖性增加。2,6-二氨基吡啶（2,6-DIAP）和3,4-二氨基吡啶（3,4-DIAP）使与4-AP相关杠杆上的反应百分比呈剂量依赖性增加，但仅部分替代4-AP。4-二甲基氨基吡啶（4-DMAP）和吡啶均不能替代4-AP。还使用间接多巴胺、去甲肾上腺素、血清素和乙酰胆碱激动剂以及γ-氨基丁酸A（GABA(A)）激动剂和拮抗剂进行了替代研究。去甲肾上腺素再摄取抑制剂托莫西汀，而非尼索西汀或丙咪嗪，使与4-AP相关杠杆上的反应百分比呈剂量依赖性增加，并部分替代4-AP。此外，使用间接多巴胺、去甲肾上腺素、血清素、乙酰胆碱拮抗剂以及GABA(A)激动剂作为4-AP训练剂量的预处理进行了拮抗研究。苯二氮䓬类激动剂氯氮卓和地西泮剂量依赖性地减弱了4-AP的DS效应。目前的结果表明，钾通道阻滞剂4-AP在大鼠中可被训练为一种DS，且4-AP的DS效应可能是通过阻断电压依赖性钾通道介导的。结果还证明了苯二氮䓬类药物与钾通道之间存在一种新的相互作用。
