去甲烟碱对大鼠运动活动的急性和慢性影响：对尼古丁反应的改变。

Acute and chronic effects of nornicotine on locomotor activity in rats: altered response to nicotine.

作者信息

Dwoskin L P, Crooks P A, Teng L, Green T A, Bardo M T

机构信息

College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.

出版信息

Psychopharmacology (Berl). 1999 Aug;145(4):442-51. doi: 10.1007/s002130051079.

DOI:10.1007/s002130051079

PMID:10460322

Abstract

RATIONALE

Nicotine, a tobacco alkaloid, is known to be important in the acquisition and maintenance of tobacco smoking. Nornicotine, an active nicotine metabolite, stimulates nicotinic receptors and may produce psychomotor effects similar to nicotine.

OBJECTIVE

The present study determined the effects of acute and repeated administration of nornicotine on locomotor activity and compared its effects with those of nicotine.

METHODS

R(+)-Nornicotine (0.3-10 mg/kg), S(-)-nornicotine (0.3-10 mg/kg), S(-)-nicotine (0.1-1 mg/kg) or saline was administered s.c. to rats acutely or repeatedly (eight injections at 48-h intervals). Activity was recorded for 50 min immediately after each injection.

RESULTS

S(-)-Nicotine produced transient hypoactivity, followed by dose-related hyperactivity. Repeated S(-)-nicotine administration resulted in tolerance to the hypoactivity and sensitization to the hyperactivity. Subsequent testing following a saline injection revealed evidence of conditioned hyperactivity. Acute administration of 0.3 mg/kg or 1 mg/kg R(+)- or S(-)-nornicotine produced no effect. Transient hypoactivity was observed at 3 mg/kg and 10 mg/kg R(+)-nornicotine and at 10 mg/kg S(-)-nornicotine. However, rebound hyperactivity was not observed following acute administration of either nornicotine enantiomer, suggesting that nornicotine-induced psychomotor effects differ qualitatively from those of S(-)-nicotine. Repeated R(+)-nornicotine resulted in tolerance to the transient hypoactivity, however hyperactivity was not observed. Repeated S(-)-nornicotine resulted in tolerance to the hypoactivity and the appearance of hyperactivity. Repeated administration of either nornicotine enantiomer resulted in a dose-dependent alteration in response to a 1 mg/kg S(-)-nicotine challenge, suggesting some commonalities in the mechanism of action.

CONCLUSION

Nornicotine likely contributes to the neuropharmacological effects of nicotine and tobacco use.

摘要

原理

尼古丁是一种烟草生物碱，已知其在吸烟的养成和维持中起着重要作用。去甲烟碱是一种活性尼古丁代谢产物，可刺激烟碱受体，并可能产生与尼古丁类似的精神运动效应。

目的

本研究确定了急性和重复给予去甲烟碱对运动活性的影响，并将其与尼古丁的影响进行比较。

方法

将R(+)-去甲烟碱（0.3 - 10毫克/千克）、S(-)-去甲烟碱（0.3 - 10毫克/千克）、S(-)-尼古丁（0.1 - 1毫克/千克）或生理盐水急性或重复（每隔48小时注射八次）皮下注射给大鼠。每次注射后立即记录50分钟的活动情况。

结果

S(-)-尼古丁产生短暂的活动减少，随后是剂量相关的活动增加。重复给予S(-)-尼古丁导致对活动减少产生耐受性，并对活动增加产生敏化作用。注射生理盐水后的后续测试显示有条件性活动增加的证据。急性给予0.3毫克/千克或1毫克/千克的R(+)-或S(-)-去甲烟碱没有效果。在3毫克/千克和10毫克/千克的R(+)-去甲烟碱以及10毫克/千克的S(-)-去甲烟碱时观察到短暂的活动减少。然而，急性给予任何一种去甲烟碱对映体后均未观察到反弹性活动增加，这表明去甲烟碱诱导的精神运动效应在性质上与S(-)-尼古丁不同。重复给予R(+)-去甲烟碱导致对短暂活动减少产生耐受性，但未观察到活动增加。重复给予S(-)-去甲烟碱导致对活动减少产生耐受性并出现活动增加。重复给予任何一种去甲烟碱对映体均导致对1毫克/千克S(-)-尼古丁激发的反应出现剂量依赖性改变，提示作用机制存在一些共性。