Grottick A J, Trube G, Corrigall W A, Huwyler J, Malherbe P, Wyler R, Higgins G A
PRBN, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
J Pharmacol Exp Ther. 2000 Sep;294(3):1112-9.
Neuronal nicotinic receptors are comprised of combinations of alpha(2-9) and beta(2-4) subunits arranged to form a pentameric receptor. Currently, the principal central nervous system (CNS) subtypes are believed to be alpha(4)beta(2) and a homomeric alpha(7) receptor, although other combinations almost certainly exist. The identity of the nicotinic receptor subtype(s) involved in the rewarding effects of nicotine are unknown. In the present study, using some recently described subtype selective nicotinic agonists and antagonists, we investigated the role of the alpha(7) nicotinic receptor in the mediation of nicotine-induced hyperactivity and self-administration in rats. The alpha(7) receptor agonists AR-R 17779 and DMAC failed to stimulate locomotor activity in both nicotine-nontolerant and -sensitized rats. In contrast, nicotine and the putative alpha(4)beta(2) subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotine-sensitized rats, the high affinity (including the alpha(4)beta(2) subtype) nicotinic antagonist dihydro-beta-erythroidine (DHbetaE), but not the selective alpha(7) antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DHbetaE, but not MLA, pretreatment reduced nicotine self-administration. Electrophysiology experiments using Xenopus oocytes expressing the human alpha(7) receptor confirmed AR-R 17779 and DMAC to be potent agonists at this site, and further studies demonstrated the ability of systemically administered AR-R 17779 to penetrate into the CNS. Taken together, these results indicate a negligible role of alpha(7) receptors in nicotine-induced hyperlocomotion and reward in the rat, and support the view for an involvement of a member from the high-affinity nicotinic receptor subclass, possibly alpha(4)beta(2). Issues such as drug potency, CNS penetration, and desensitization of the alpha(7) receptor are discussed.
神经元烟碱型受体由α(2 - 9)和β(2 - 4)亚基组合而成，排列形成五聚体受体。目前，尽管几乎肯定存在其他组合，但主要的中枢神经系统（CNS）亚型被认为是α(4)β(2)和同聚体α(7)受体。参与尼古丁奖赏效应的烟碱型受体亚型的身份尚不清楚。在本研究中，我们使用一些最近描述的亚型选择性烟碱激动剂和拮抗剂，研究了α(7)烟碱型受体在介导尼古丁诱导的大鼠多动和自我给药中的作用。α(7)受体激动剂AR - R 17779和DMAC在尼古丁非耐受和敏感大鼠中均未能刺激运动活性。相比之下，尼古丁和假定的α(4)β(2)亚型选择性激动剂SIB1765F在两种实验条件下均增加了活性。在尼古丁敏感大鼠中，高亲和力（包括α(4)β(2)亚型）烟碱拮抗剂二氢 - β - 刺桐碱（DHβE），而非选择性α(7)拮抗剂甲基黄连碱（MLA），拮抗了尼古丁诱导的多动。同样，DHβE预处理而非MLA预处理降低了尼古丁的自我给药。使用表达人α(7)受体的非洲爪蟾卵母细胞进行的电生理实验证实AR - R 17779和DMAC在此位点是强效激动剂，进一步研究表明全身给药的AR - R 17779能够穿透进入中枢神经系统。综上所述，这些结果表明α(7)受体在大鼠尼古丁诱导的过度运动和奖赏中作用可忽略不计，并支持高亲和力烟碱型受体亚类中的一个成员（可能是α(4)β(2)）参与其中的观点。还讨论了诸如药物效力、中枢神经系统穿透和α(7)受体脱敏等问题。
