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（甲基苯丙胺）滥用是我们国家的一种流行病，为此尚待开发有效的药物治疗。精神分裂症患者对滥用兴奋剂的倾向越来越大，这种使用导致持续的精神分裂症症状加剧，并增加了（以前控制的）精神病的复发率增加。当前的应用是基于以下想法：在这种双重诊断的情况下，可以通过减少药物服用动机来提供治疗益处。抗多巴胺治疗显然还不够。代谢性谷氨酸受体I组I亚型5（MGLUR5）至关重要。参与与精神分裂症神经病理学相关的刺激性渴望和奖励以及感觉运动缺陷；因此，用于MGLUR5'的负变构调节剂（NAM）是精神分裂症患者中甲基成瘾疗法的可信候选者。这些代理具有更大的选择性和更好的副作用：比传统拮抗剂疗法相比。这笔赠款的目的是确定大鼠是否应考虑使用MGLUR5来治疗人类滥用甲基甲基苯丙胺，尤其是精神分裂症的甲基苯丙胺滥用。在目标中，将采用一种新型范式来识别人类双诊断的大鼠模型。为此，大鼠将经过重复的间歇性治疗（或否则，苯二肽），以产生通过预硫酸盐抑制（PPI）测量的感觉运动缺陷。然后，PPI分数将被评估为“高”和“低”响应者。随后，所有大鼠都将经历甲基苯丙胺引起的条件位置偏好（CPP）。我们预测，高PPI +鲁棒CPP将被视为合并症的大鼠模型。 MGLUR5（MPEP，Fenobam或SIB-1757）的NAM将在甲基苯酚调节后进行给药，以确定治疗是否可以减少随后的测试CPP。还将确定“归一化”随后的PPI的潜力。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目标I范式有关。关注最可能的区域，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性的功效相关。 AIM III将确定谷氨酸能传播的强度和/或神经递质的释放是否会改变合并症大鼠的强度，并且是否通过评估对兴奋性脉冲促进的兴奋性脉冲促进性，该改变将通过MGLUR5 NAM治疗进行标准化。我们不仅将确定MGLURR5 NAM的潜力废除精神分裂症中的甲基滥用，而且还为有助于这种共同生病的神经元机制提供了重要的新见解。