LOBELINE ANALOGS AND AMPHETAMINE SELF ADMINISTRATION

神经科学家设计了创造性的程序来调查药物滥用。 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。 本提案将研究与大鼠自我给药安非他明相关的问题。 Alpha-lobeline 是一种源自印度烟草植物的烟草生物碱。 Lobeline (LOB) 具有与安非他明相似的神经药理学特征：两者都是囊泡单胺转运蛋白 (VMAT2) 的有效抑制剂。 然而，山梗菜碱不会像安非他明那样引起多巴胺外流，而是会导致释放多巴胺（DOPAC），一种不具有强化作用的多巴胺代谢产物。靶向 VMAT2 可能是治疗安非他明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好测量的安非他明强化作用。 本实验将检验 LOB 的预处理是否会减弱大鼠体内苯丙胺的自我给药。 由于LOB对烟碱受体具有高亲和力，因此已经合成了LOB的结构类似物，其不与烟碱受体相互作用，但抑制多巴胺的摄取，并可用于研究。 本研究将通过多巴胺摄取测定确定这些类似物是否有效抑制 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。据推测，LOB和LOB类似物的预处理将减少可通过随后施用苯丙胺释放的胞质多巴胺池，从而减少苯丙胺自我施用。

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.