mGluR5 Regulation of METH Reward and Sensorimotor Gating

描述（由申请人提供）：甲基苯丙胺（Methe）滥用在我国是一种流行病，有效的药物治疗尚未开发。精神分裂症患者滥用兴奋剂的倾向增加，这种使用导致正在进行的精神分裂症症状加重，并增加（先前控制的）精神病复发的发生率。本申请基于这样的想法，即在这种双重诊断的情况下，通过减少吸毒的动机将提供治疗益处。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（mGluR 5）是关键的。参与了与精神分裂症神经病理学相关的刺激物渴求和奖赏以及感觉运动缺陷;因此，mGluR 5 ′的负变构调节剂（NAM）是精神分裂症患者中甲基成瘾治疗的可靠候选者。这些药物提供了更大的选择性和更好的副作用：比传统的拮抗剂疗法。本研究的目的是在大鼠中确定mGluR 5的NAM是否应考虑用于治疗人类甲基滥用，特别是精神分裂症中的甲基滥用。目的一：建立一种新的人类双重诊断大鼠模型。为此，将对大鼠进行苯丙胺（或苯环利定）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”应答者的PPI评分。随后，所有大鼠将经历Meth-induced conditioned place preference（CPP）。我们预测，高PPI +稳健的Meth CPP将被视为共病的大鼠模型。将在甲基处理后给予mGluR 5的NAM（MPEP、非诺班或SIB-1757），以确定治疗是否可以降低后续测试CPP。随后PPI“正常化”的可能性也将确定。对于Aim II，将使用免疫印迹方法来确定大脑边缘区域内mGluR 5表面表达的变化是否与最佳Aim I范例相关。重点关注最有可能的区域，将使用体内电生理学来确定表面表达是否与mGluR 5激动剂改变神经元活动的功效相关。目的III将确定在共病大鼠中是否改变了谷氨酸能传递和/或神经递质释放的强度，以及通过评估体内细胞内记录的兴奋性突触后电位的成对脉冲促进，这种改变是否将通过mGluR 5 NAM治疗而正常化。我们将不仅确定了mGlurR 5的NAM消除精神分裂症中的甲基滥用的潜力，而且还提供了对导致这种共病的神经元机制的重要新见解。

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.