Biochemistry Of Ligand Gated Ion Channels Important To D

尼古丁乙酰胆碱受体是尼古丁作用的配体门控离子通道，在尼古丁滥用中起着重要作用，了解其神经生物学可能是开发更合理的尼古丁滥用治疗方法的关键。受体-配体相互作用的体外表征是理解配体体内作用的重要步骤（即，用于解释来自受体的功能研究的结果）。 在对吸烟的精神分裂症患者的脑组织的研究中发现，与精神健康的吸烟者的脑组织相比，烟碱乙酰胆碱受体的上调较少。由于精神分裂症患者经常长期服用典型或非典型的精神抑制剂，因此在大鼠中测试了这些药物对尼古丁上调α 4 β 2 * 烟碱受体的影响。文献报告表明，典型的精神抑制剂氟哌啶醇没有效果。我们使用5-[I-125]碘-A-85380进行体外试验，测试了非典型神经安定药利培酮和奥氮平对尼古丁上调大鼠丘脑、纹状体和海马中这些受体的影响。这两种药物都没有减弱尼古丁的作用，尼古丁分别使这些区域的受体密度增加了50%、80%和90%;然而，在没有尼古丁的情况下给予利培酮，纹状体中的烟碱受体密度适度增加（25%）。 大量轶事证据表明，尼古丁可能是非法使用毒品的入门药物。利用药物奖赏的动物食饵动物模型，已经建立了条件性位置偏爱（CPP），尼古丁对阿片类药物产生交叉致敏作用。我们利用CPP来检验尼古丁对不同类别的滥用药物（特别是兴奋剂）产生行为交叉致敏的假设。在大鼠中进行的这些实验表明，尼古丁预处理可在停用尼古丁后至少3至5天内增强苯丙胺的奖励效应，该效应在19天内消失。潜在的机制涉及α 4 β 2烟碱乙酰胆碱受体，因为竞争性α 4 β 2拮抗剂二氢β赤藓定有效地阻断了尼古丁诱导的交叉致敏作用的发展。有趣的是，在大鼠中，α 7烟碱拮抗剂methylylycaconitine在不阻断尼古丁自我给药的剂量下也可拮抗交叉致敏作用。本研究和已发表的报告明确表明，尼古丁对阿片类药物和精神兴奋剂的奖励作用产生交叉致敏作用，并使用CPP进行测量。对这些药物的奖励作用的交叉致敏的发展涉及尼古丁与α 4 β 2和可能的α 7烟碱乙酰胆碱受体的相互作用，这与尼古丁自我给药不同，尼古丁自我给药主要由α 4 β 2受体介导。

Nicotinic acetylcholine receptors, the ligand gated ion channels at which nicotine acts, play an important role in nicotine abuse and understanding its neurobiology may be central to developing more rational approaches for nicotine abuse treatments. The in vitro characterization of the receptor-ligand interaction is an important step in understanding the action of a ligand in vivo (i.e., for interpretation of the results from the functional studies of receptors). Less upregulation of nicotinic acetylcholine receptors is found in studies of brain tissue from patients with schizophrenia who smoke than in brain tissue from mentally healthy smokers. As schizophrenic patients often take typical or atypical neuroleptics chronically, the impact of these drugs on the upregulation of alpha4beta2* nicotinic receptors by nicotine was tested in rats. Literature reports suggest that the typical neuroleptic, haloperidol, has no effect. We tested the effect of the atypical neuroleptics, risperidone and olanzapine on the upregulation of these receptors by nicotine in the thalamus, striatum and hippocampus of rats using in vitro assays with 5-[I-125]iodo-A-85380. Neither drug attenuated the effect of nicotine, which increased the density of the receptors in these areas by 50, 80 and 90%, respectively; however, risperidone given without nicotine produced a modest increase (25%) in the density of the nicotinic receptors in the striatum. Substantial anecdotal evidence suggests that nicotine may function as a gateway drug to illicit drug use. It has been established, using an animal behavorial model of drug rewards, conditioned place preference (CPP) that nicotine produces cross sensitization to opioids. We utilized CPP to test the hypothesis that nicotine produces behavioral cross sensitization to a different class of abused drugs, specifically stimulants. These experiments in rats demonstrated that nicotine pretreatment enhances the rewarding effects of amphetamine for at least 3 to 5 days following the cessation of nicotine, with this effect dissipating within 19 days. The underlying mechanism involves alpha4beta2 nicotinic acetylcholine receptors as the competitive alpha4beta2 antagonist dihydro beta erythroidine effectively blocked the development of nicotine-induced cross sensitization. Interestingly, the alpha7 nicotinic antagonist methyllycaconitine also antagonized cross-sensitization at doses that do not block nicotine self-administration in rats. This study and published report have clearly demonstrated that nicotine produces cross-sensitization to the rewarding effects of both opiates and psychostimulants measured with CPP. The development of cross-sensitization to the rewarding effects of these drugs involves the interaction of nicotine with alpha4beta2 and probably alpha7 nicotinic acetylcholine receptors, differing from niccotine self-administration, which is primarily mediated by alpha4beta2 receptors.