mGluR5 Regulation of METH Reward and Sensorimotor Gating

mGluR5 对 METH 奖励和感觉运动门控的调节

• 批准号: 7633169
• 负责人: Amy Herrold
• 金额: $ 2.35万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-16 至 2010-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633169
• 关键词: Adverse effects; Agonist; Americas; Amphetamines; Antipsychotic Agents; Applications Grants; Behavior; Behavioral; Brain; Brain region; Chronic; Disease; Dopamine; Drug Addiction; Electrophysiology (science); Epidemic; Excitatory Postsynaptic Potentials; Exhibits; Experimental Designs; Glutamates; Goals; Grant; Human; Immunoblotting; Incidence; Ligands; Light; Limbic System; Measures; Metabotropic Glutamate Receptors; Methamphetamine; Modeling; Morbidity - disease rate; Neurons; Neurotransmitters; Normalcy; Outcome; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phencyclidine; Physiologic pulse; Predictive Value; Process; Proteins; Psychostimulant dependence; Psychotic Disorders; Rattus; Regulation; Relapse; Relative (related person); Reporting; Rewards; Risk; Rodent; Rodent Model; Schizophrenia; Scientific Advances and Accomplishments; Substance abuse problem; Surface; Symptoms; Synapses; System; Testing; Therapeutic; Time; Translating; Western Blotting; addiction; clinical efficacy; conditioning; craving; dual diagnosis; fenobam; in vivo; indexing; insight; mature animal; meetings; methamphetamine abuse; neuropathology; neurotransmitter release; new therapeutic target; novel; preference; prepulse inhibition; presynaptic; psychostimulant; receptor; receptor upregulation; stimulant abuse; therapeutic target; transmission process

DESCRIPTION (provided by applicant): Methamphetamine (Meth) abuse is an epidemic in our nation, for which an effective pharmacotherapy is yet to be developed. Schizophrenics have an increased propensity to abuse stimulants, and this use results in exacerbation of ongoing schizophrenic symptoms and an increased incidence of relapse to (previously controlled) psychosis. The current application is predicated on the idea that therapeutic benefit would be provided in cases of such dual-diagnosis by reducing the motive for drug taking. Anti-dopamine treatments clearly are not sufficient. The metabotropic glutamate receptor group I subtype 5 (mGluR5) is critically . involved in stimulant craving and reward as well as sensorimotor deficits associated with schizophrenia neuropathology; thus, negative allosteric modulators (NAM) for mGluR5' are credible candidates for Meth addiction therapy in the schizophrenic patient. These agents offer greater selectivity and better side effect : profiles than traditional antagonist therapies. The objective of this grant is to determine in rats if NAM-for the mGluR5 should be considered for the treatment of Meth abuse in humans, in particular Meth abuse in schizophrenia. In Aim I a novel paradigm to identify rat model of human dual-diagnosis will be employed. To do so, rats will be subjected to repeated intermittent treatment of amphetamine (or alternatively, phencyclidine) to produce sensorimotor deficits that measured via prepulse inhibition (PPI). PPI scores will then be assessed for "high" and "low" responders. Subsequently, all rats will undergo Meth-induced conditioned place preference (CPP). We predict that high PPI + robust Meth CPP will be considered as a rat model of co-morbidity. NAM of mGluR5 (MPEP, fenobam, or SIB-1757) will be administered after Meth conditioning to determine if the treatment can reduce subsequent testing CPP. The potential for 'normalizing' subsequent PPI also will be determined. For Aim II, immunoblotting approaches will be used to determine if changes in mGluR5 surface expression within limbic regions of the brain are associated with the optimal Aim I paradigm. Focusing on the most likely region, in vivo electrophysiology will be used to determine if surface expression is correlated to efficacy of mGluR5 agonists to alter neuronal activity. Aim III will determine if the strength of glutamatergic transmission and/or neurotransmitter release is altered in co-morbid rats and if this alteration will be normalized with mGluR5 NAM treatment via assessment of paired pulse facilitation of excitatory postsynaptic potentials recorded intracellularly in vivo. We will have not only identified the potential of NAM of mGlurR5 for abrogating Meth-abuse in schizophrenia, but also provided important new insights into the neuronal mechanisms that contribute to this co-morbidity.

描述（由申请人提供）：甲基苯丙胺（Meth）滥用在我国是一种流行病，目前尚未开发出有效的药物疗法。精神分裂症患者滥用兴奋剂的倾向增加，这种使用会导致持续的精神分裂症症状恶化，并增加（先前控制的）精神病复发的发生率。当前的应用基于这样的想法：在这种双重诊断的情况下，将通过减少吸毒的动机来提供治疗益处。抗多巴胺治疗显然是不够的。代谢型谷氨酸受体 I 组亚型 5 (mGluR5) 至关重要。涉及刺激性渴望和奖励以及与精神分裂症神经病理学相关的感觉运动缺陷；因此，mGluR5' 的负变构调节剂 (NAM) 是精神分裂症患者冰毒成瘾治疗的可靠候选者。与传统的拮抗剂疗法相比，这些药物具有更高的选择性和更好的副作用。这笔资助的目的是在大鼠中确定是否应考虑将 NAM-for mGluR5 用于治疗人类的冰毒滥用，特别是精神分裂症中的冰毒滥用。在目标 I 中，将采用一种新的范例来识别人类双重诊断的大鼠模型。为此，大鼠将接受苯丙胺（或苯环己哌啶）的重复间歇治疗，以产生通过前脉冲抑制（PPI）测量的感觉运动缺陷。然后将评估“高”和“低”响应者的 PPI 分数。随后，所有大鼠将经历冰毒诱导的条件性位置偏好（CPP）。我们预测高 PPI + 稳健的 Meth CPP 将被视为共病的大鼠模型。在冰毒调理后将施用 mGluR5（MPEP、非诺巴姆或 SIB-1757）的 NAM，以确定该治疗是否可以减少后续检测的 CPP。后续 PPI“正常化”的可能性也将被确定。对于 Aim II，将使用免疫印迹方法来确定大脑边缘区域内 mGluR5 表面表达的变化是否与最佳 Aim I 范例相关。着眼于最可能的区域，体内电生理学将用于确定表面表达是否与 mGluR5 激动剂改变神经元活动的功效相关。目标 III 将确定共病大鼠中谷氨酸传递和/或神经递质释放的强度是否发生改变，以及通过评估体内细胞内记录的兴奋性突触后电位的配对脉冲促进作用，这种改变是否会通过 mGluR5 NAM 治疗而正常化。我们不仅会发现 mGlurR5 的 NAM 在消除精神分裂症中冰毒滥用方面的潜力，而且还会为导致这种共病的神经元机制提供重要的新见解。