Reboxetine: Attenuation of intravenous nicotine self-administration in rats
Reboxetine: Attenuation of intravenous nicotine self-administration in rats
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DOI：
10.1124/jpet.303.2.664
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发表时间：
2002-11-01
影响因子：
3.5
通讯作者：
Bardo, MT
中科院分区：
文献类型：
--
作者：
Rauhut, AS;Mullins, SN;Bardo, MT
瑞波西汀是一种去甲肾上腺素转运蛋白的选择性抑制剂，也是一种神经元烟碱受体的非竞争性拮抗剂，它改变大鼠尼古丁自我给药的能力与美加明（一种经典的烟碱受体非竞争性拮抗剂）进行了比较。还检查了瑞波西汀改变蔗糖维持反应的能力，以评估对尼古丁自我给药影响的特异性。以固定比率5时间表训练大鼠以自我施用尼古丁（0.02 mg/kg/输注i.v.）或对蔗糖颗粒有反应。在达到稳定的基线后，在阶段前15分钟用载体、瑞波西汀（外消旋）、（+）-（S，S）-瑞波西汀（0.3 - 30 mg/kg s. c.）或美加明（0.5 - 4mg/kg s.（c）。为了评估重复给药的效果，在尼古丁自我给药或蔗糖维持反应之前，每天注射一次瑞波西汀（5.6 mg/kg），连续14次。通过检查重复给予瑞波西汀（5.6 mg/kg）改变尼古丁诱导的活动过度（0.8 mg/kg）的能力，进一步评估特异性。瑞波西汀、（+）-（S，S）-瑞波西汀和美加明剂量依赖性地减少尼古丁自我给药，减少幅度接近60%，而瑞波西汀和（+）（S，S）-瑞波西汀在较小程度上减少了蔗糖维持反应（类似于20%）。重复给予瑞波西汀（5.6 mg/kg）降低了14个阶段的尼古丁自我给药和蔗糖维持反应，表明对瑞波西汀的这些作用没有产生耐受性。此外，瑞波西汀没有改变基线自发活动，表明尼古丁和蔗糖的操作性反应降低不是活动非特异性降低的结果。瑞波西汀诱导的尼古丁自我给药和蔗糖维持反应减少可能是去甲肾上腺素转运蛋白和/或神经元烟碱受体功能抑制的结果。
The ability of reboxetine, a selective inhibitor of the norepinephrine transporter and noncompetitive antagonist at neuronal nicotinic receptors, to alter nicotine self-administration in rats was compared with that of mecamylamine, a classical noncompetitive antagonist at nicotinic receptors. The ability of reboxetine to alter sucrose-maintained responding was also examined to assess the specificity of the effect on nicotine self-administration. Rats were trained on a fixed ratio 5 schedule to self-administer nicotine (0.02 mg/kg/infusion i.v.) or to respond for sucrose pellets. Upon reaching a stable baseline, rats were pretreated 15 min before the session with vehicle, reboxetine (racemic), (+)-(S, S)-reboxetine (0.3-30 mg/kg s. c.) or mecamylamine (0.5-4 mg/kg s. c). To assess the effect of repeated administration, reboxetine (5.6 mg/kg) was injected once daily for 14 consecutive sessions before either nicotine self-administration or sucrose-maintained responding. Specificity was further assessed by examining the ability of repeated administration of reboxetine (5.6 mg/kg) to alter nicotine-induced hyperactivity (0.8 mg/kg). Reboxetine, (+)-(S,S)-reboxetine, and mecamylamine dose dependently decreased nicotine self-administration by similar to60%, whereas reboxetine and (+) ( S, S)- reboxetine decreased sucrose-maintained responding to a lesser extent (similar to20%). Repeated administration of reboxetine (5.6 mg/kg) decreased nicotine self-administration and sucrose-maintained responding across the 14 sessions, suggesting that tolerance did not develop to these effects of reboxetine. Additionally, reboxetine did not alter baseline locomotor activity, indicating that the decrease in operant responding for nicotine and sucrose was not the result of a nonspecific decrease in activity. The reboxetine-induced decrease in nicotine self-administration and sucrose-maintained responding may be the result of inhibition of norepinephrine transporters and/or neuronal nicotinic receptor function.