mGluR5 Regulation of METH Reward and Sensorimotor Gating

描述(申请人提供)：甲基苯丙胺(Meth)滥用在我国是一种流行病，针对这一现象的有效药物治疗尚未开发出来。精神分裂症患者滥用兴奋剂的倾向增加，这种使用会导致正在进行的精神分裂症症状的恶化和(以前控制的)精神病复发的增加。目前的应用是基于这样一个想法，即通过减少吸毒动机，将在这种双重诊断的情况下提供治疗益处。抗多巴胺治疗显然是不够的。代谢型谷氨酸受体I亚型5(MGluR5)是至关重要的。与精神分裂症神经病理相关的刺激渴望和奖励以及感觉运动缺陷有关；因此，mGluR5‘的负变构调节器(NAM)是精神分裂症患者Meth成瘾治疗的可靠候选者。这些药物提供了更好的选择性和更好的副作用：与传统的拮抗剂疗法相比。这项拨款的目的是在大鼠身上确定是否应该考虑将mGluR5的NAM-for mGluR5用于治疗人类的Meth滥用，特别是精神分裂症中的Meth滥用。在AIM I中，将采用一种新的范式来识别人类双重诊断的大鼠模型。为了做到这一点，大鼠将受到苯丙胺(或苯环利定)的反复间歇治疗，以产生通过脉冲前抑制(PPI)测量的感觉运动缺陷。然后将评估PPI分数，以确定“高”和“低”应答者。随后，所有大鼠都将接受Meth诱导的条件性位置偏爱(CPP)。我们预测，高PPI+健壮的Meth CPP将被认为是一种共同发病的大鼠模型。MGluR5(MPEP、Fenobam或SIB-1757)的NAM将在Meth预适应后给予，以确定该治疗是否可以减少后续的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mGluR5表面表达的变化是否与AIM I的最佳范例有关。关注最有可能的区域，体内电生理学将被用来确定表面表达是否与mGluR5激动剂改变神经元活动的疗效相关。目的III将通过对细胞内记录的兴奋性突触后电位的成对脉冲易化的评估，确定共病大鼠谷氨酸能传递和/或神经递质释放的强度是否改变，以及mGluR5 NAM治疗是否能使这种改变正常化。我们不仅将确定mGlurR5的NAM在精神分裂症中消除甲基滥用的潜力，而且还将为导致这种共同发病的神经机制提供重要的新见解。

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.