LOBELINE ANALOGS AND AMPHETAMINE SELF ADMINISTRATION

神经科学家发明了一种新的方法来研究药物滥用。一种程序，自我给药模型，是检验药物自我给药机制和治疗的有用技术。本提案将调查与安非他明自我给药大鼠有关的问题。红叶碱是一种从印度烟草植物中提取的烟草生物碱。洛贝林（LOB）与安非他明具有相似的神经药理学特征：两者都是水疱单胺转运蛋白（VMAT2）的有效抑制剂。然而，它不像安非他明那样引起多巴胺外溢，而是导致多巴胺的代谢物多巴胺的释放，多巴胺不会增强。靶向VMAT2可能是治疗安非他明滥用的一种有希望的方法，因为缺乏VMAT2的小鼠不会表现出安非他明强化的效果，通过条件位置偏好测量。本实验将探讨LOB预处理是否会减弱大鼠对安非他明的自我给药。由于LOB对尼古丁受体具有高亲和力，因此已经合成了LOB的结构类似物，这些类似物不与尼古丁受体相互作用，但能抑制多巴胺的摄取，并可供研究。目前的研究将通过多巴胺摄取测定来确定这些类似物是否能有效抑制VMAT2的多巴胺摄取。与LOB相比，LOB类似物减少安非他明自我给药的能力也将被研究。假设LOB和LOB类似物的预处理会减少随后给药安非他明释放的多巴胺的胞质池，从而减少安非他明的自我给药。

Neuroscientists have devised inventive procedures to investigate drugs of abuse. One procedure, the self administration model, is a useful technique to examine mechanisms and treatment of drug self administration. The present proposal will investigate issues related to amphetamine self-administration in rats. Alpha-lobeline is a tobacco alkaloid derived from an Indian tobacco plant. Lobeline (LOB) has a similar neuropharmacological profile as amphetamine: both are potent inhibitors of the vesicular monoamine transporter (VMAT2). However, rather than evoking dopamine efflux like that of amphetamine, lobeline results in the release DOPAC, a metabolite of dopamine which is not reinforcing. Targeting VMAT2 may be a promising approach in the treatment of amphetamine abuse, as mice that lack VMAT2 do not exhibit the effects of amphetamine reinforcement as measured through conditioned place preference. The present experiments will examine whether pretreatment of LOB will attenuate amphetamine self-administration in rats. Since LOB has a high affinity for nicotine receptors, structural analogs of LOB which are devoid of nicotinic receptor interaction, but which inhibit dopamine uptake, have been synthesized and are available for study. The present research will determine whether these analogs potently inhibit dopamine uptake at VMAT2 by using a dopamine uptake assay. The LOB analogs ability to decrease amphetamine self-administration, in comparison to LOB, will also be investigated. It is hypothesized that pretreatment of LOB and LOB analogs will reduce the cytosolic pool of dopamine available for release by subsequent administration of amphetamine, and thereby reduce amphetamine self-administration.