Preclinical Pharmacology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts.
Preclinical Pharmacology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts
J Pharmacol Exp Ther. 2018 Aug;366(2):397-409. doi: 10.1124/jpet.118.248070. Epub 2018 May 21.
Evidence suggests that the 42, but not the 7, subtype of the nicotinic acetylcholine receptor (nAChR) plays a key role in mediating the behavioral effects of nicotine and related drugs. However, the importance of other nAChR subtypes remains unclear. The present studies were conducted to examine the involvement of nAChR subtypes by determining the effects of selected nicotinic agonists and antagonists in squirrel monkeys either 1) responding for food reinforcement or 2) discriminating the nicotinic agonist (+)-epibatidine (0.001 mg/kg) from vehicle. In food-reinforcement studies, nicotine, (+)-epibatidine, varenicline and cytisine all produced dose-dependent decreases in rates of food-maintained responding. The rate-decreasing effects of nicotine were antagonized by mecamylamine (nonselective), not appreciably altered by dihydro--erythroidine (42 selective), and exacerbated by the nicotinic partial agonists, varenicline and cytisine. Results from discrimination studies show that non-nicotinic drugs did not substitute for (+)-epibatidine, and that except for lobeline, the nicotinic agonists produced either full [(+)-epibatidine, (-)-epibatidine, and nicotine] or partial (varenicline, cytisine, anabaseine, and isoarecolone) substitution for (+)-epibatidine. In interaction studies with antagonists differing in selectivity, (+)-epibatidine discrimination was substantively antagonized by mecamylamine, slightly attenuated by hexamethonium (peripherally restricted) or dihydro--erythroidine, and not altered by methyllycaconitine (7 selective). Varenicline and cytisine enhanced (+)-epibatidine's discriminative-stimulus effects. Correlational analysis revealed a close correspondence between relative behavioral potencies of nicotinic agonists in both studies and their published relative binding affinities at 42 and 34, but not 7 nAChR, subtypes. Collectively, these results are consistent with the idea that the 42 and 34, but not 7 nAChR subtypes play a role in the behavioral effects of nicotinic agonists.
有证据表明，尼古丁型乙酰胆碱受体（nAChR）的 42 亚型而非 7 亚型在介导尼古丁和相关药物的行为效应中起着关键作用。然而，其他 nAChR 亚型的重要性仍不清楚。本研究通过测定选定的烟碱激动剂和拮抗剂在松鼠猴中的作用，来研究 nAChR 亚型的参与情况，这些作用包括：1）对食物强化的反应或 2）对烟碱激动剂 (+)-epibatidine（0.001 mg/kg）与载体的区分。在食物强化研究中，尼古丁、(+) - epibatidine、伐仑克林和 cytisine 均产生剂量依赖性地降低食物维持反应的速率。尼古丁的这种降低作用被美加明（非选择性）拮抗，而二氢--erythroidine（42 选择性）则没有明显改变，并且被烟碱部分激动剂伐仑克林和 cytisine 加剧。辨别研究的结果表明，非烟碱类药物不能替代 (+)-epibatidine，除了 lobeline 之外，烟碱激动剂产生了 (+)-epibatidine 的完全（(+) - epibatidine、(-)-epibatidine 和尼古丁）或部分（伐仑克林、cytisine、anabaseine 和异常山酮）替代。在与选择性不同的拮抗剂的相互作用研究中，(+) - epibatidine 的辨别被美加明实质性拮抗，被六烃季铵（外周受限）或二氢--erythroidine 轻微减弱，而被甲基lycaconitine（7 选择性）不改变。伐仑克林和 cytisine 增强了 (+)-epibatidine 的辨别性刺激作用。相关分析表明，在这两项研究中，烟碱激动剂的相对行为效力与它们在 42 和 34 但不是 7 nAChR 亚型上的相对结合亲和力之间存在密切对应关系。总的来说，这些结果与这样一种观点一致，即 42 和 34 但不是 7 nAChR 亚型在烟碱激动剂的行为效应中发挥作用。
