LOBELINE ANALOGS AND AMPHETAMINE SELF ADMINISTRATION

神经学家发明了调查滥用药物的独创性方法。自我给药模型是一种检查药物自我给药机制和治疗的有用技术。本提案将调查与苯丙胺在大鼠体内自我给药有关的问题。阿尔法-洛贝林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：两者都是囊泡单胺转运体(VMAT2)的有效抑制剂。然而，洛贝林不是像安非他明那样引起多巴胺外流，而是导致释放DOPAC，这是多巴胺的一种代谢物，不会增强。靶向VMAT2可能是治疗苯丙胺滥用的一种有前途的方法，因为缺乏VMAT2的小鼠不会表现出通过条件性位置偏爱来衡量的苯丙胺强化的效果。目前的实验将检验LOB的预处理是否会减弱大鼠的苯丙胺自我给药。由于LOB对尼古丁受体有很高的亲和力，因此人们已经合成了一些结构类似的LOB，它们不存在尼古丁受体的相互作用，但可以抑制多巴胺的摄取，可以用于研究。目前的研究将通过使用多巴胺摄取试验来确定这些类似物是否有效地抑制VMAT2的多巴胺摄取。与LOB相比，LOB类似物减少苯丙胺自我给药的能力也将被调查。据推测，LOB和LOB类似物的预处理将减少随后给药苯丙胺可释放的细胞内多巴胺池，从而减少苯丙胺的自我给药。

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.