LOBELINE ANALOGS AND AMPHETAMINE SELF ADMINISTRATION

神经科学家发明了一些新的方法来调查滥用药物的情况。 一个程序，自我管理模式，是一个有用的技术来检查机制和药物自我管理的治疗。 本提案将调查与大鼠苯丙胺自我给药有关的问题。α-洛贝林是来自印度烟草植物的烟草生物碱。 洛贝林（LOB）具有与苯丙胺相似的神经药理学特征：两者都是囊泡单胺转运蛋白（VMAT 2）的强效抑制剂。 然而，洛贝林不是像安非他明那样引起多巴胺流出，而是导致释放DOPAC，这是多巴胺的代谢产物，不是强化。靶向VMAT 2可能是治疗安非他明滥用的一种有前途的方法，因为缺乏VMAT 2的小鼠不表现出安非他明强化的效果，如通过条件性位置偏好所测量的。 本实验将检查LOB的预处理是否会减弱大鼠中的苯丙胺自我给药。 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，其不具有烟碱受体相互作用，但抑制多巴胺摄取，并可用于研究。 本研究将通过使用多巴胺摄取测定来确定这些类似物是否有效地抑制VMAT 2处的多巴胺摄取。 还将研究与LOB相比，LOB类似物减少安非他明自我给药的能力。据推测，LOB和LOB类似物的预处理将减少可用于随后施用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.