mGluR5 Regulation of METH Reward and Sensorimotor Gating

描述（申请人提供）：甲基苯丙胺（冰毒）滥用在我国是一种流行病，尚未开发出有效的药物治疗方法。精神分裂症患者滥用兴奋剂的倾向增加，这种使用导致持续的精神分裂症症状加剧和（先前控制的）精神病复发的发生率增加。目前的应用是基于这样一种想法，即通过减少服药动机，可以为双重诊断的病例提供治疗益处。抗多巴胺治疗显然是不够的。代谢性谷氨酸受体I亚型5 （mGluR5）是至关重要的。参与兴奋剂渴求和奖励以及与精神分裂症神经病理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。与传统的拮抗剂相比，这些药物具有更高的选择性和更好的副作用。这项拨款的目的是在大鼠中确定mGluR5的nam是否应该被考虑用于治疗人类的冰毒滥用，特别是精神分裂症的冰毒滥用。在目的1中，将采用一种新的范式来识别人类双重诊断的大鼠模型。为此，大鼠将反复接受安非他明（或苯环利定）的间歇性治疗，以产生通过脉冲前抑制（PPI）测量的感觉运动缺陷。然后评估PPI得分为“高”和“低”反应者。随后，所有大鼠进行冰毒诱导的条件位置偏好（CPP）实验。我们预测，高PPI +稳健的甲基苯丙胺CPP将被认为是合并症的大鼠模型。mGluR5的NAM （MPEP，非诺巴姆或sibb -1757）将在冰毒调节后给予，以确定治疗是否可以降低随后的测试CPP。随后PPI“正常化”的可能性也将被确定。对于Aim II，免疫印迹方法将用于确定大脑边缘区域mGluR5表面表达的变化是否与最佳Aim I范式相关。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动的功效相关。Aim III将通过评估细胞内记录的兴奋性突触后电位的配对脉冲促进，确定在共病大鼠中谷氨酸能传递和/或神经递质释放的强度是否改变，以及这种改变是否会在mGluR5 NAM治疗后正常化。我们不仅确定了mGlurR5的NAM在消除精神分裂症患者滥用冰毒方面的潜力，而且还为导致这种合并症的神经元机制提供了重要的新见解。

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.