Reversal of Methamphetamine Induced Cognitive Deficits and mGlu Receptors

描述（由申请人提供）： 在慢性吸毒成瘾者中观察到的甲基苯丙胺引起的认知障碍是甲基苯丙胺成瘾和治疗中特别严重的问题。因此，需要进行研究努力以开发与人类甲基成瘾中观察到的认知障碍具有翻译相关性的动物模型。临床前动物模型揭示了大鼠识别记忆的长期损害。具体来说，高剂量的非偶然的冰毒注射会产生神经毒性，破坏记忆任务的表现。大多数物体识别研究使用短期，非偶然的药物递送方法来研究冰毒对识别记忆的影响。静脉内冰毒自我管理提供了一种翻译方法，作为人类冰毒成瘾和慢性冰毒对认知功能影响的模型。初步研究表明，偶然长时间接触冰毒会导致识别记忆的缺陷，而冰毒的摄入与24小时后的记忆缺陷有关。这个提议的目的之一是确定这些识别记忆的缺陷是否涉及一种神经元能机制。为了逆转甲基苯丙胺诱导的识别记忆缺陷，Specific Aim 1将在获得新物体识别期间使用代谢型谷氨酸受体（mGluR）2/3激动剂，Specific Aim 2将使用mGluR 5阳性变构调节剂。此外，本提案中的实验将鉴定与冰毒成瘾相关的脑区域中冰毒诱导的mGluR 2/3和5表达的变化（即，背侧纹状体，和前额叶皮层）和识别记忆（即，嗅周皮层和海马体）。将检查甲安菲他明摄入量、物体识别分数和受体水平的相关性和预测关系。确定这种关系将为甲基诱导的认知缺陷提供新的见解，阐明潜在的神经元机制，并有助于确定这种动物模型中可能的治疗干预。 公共卫生相关性： 项目叙述这些研究的总体目的是确定随着时间的推移有动机的冰毒服用行为、冰毒诱导的认知障碍和潜在的神经机制之间的关系。使用甲基成瘾的转化动物模型允许研究甲基成瘾中表现出的认知和动机缺陷。此外，识别与这种翻译模型有关的神经机制可能有助于识别有前途的新药物靶点，用于治疗甲基苯丙胺诱导的认知障碍。

DESCRIPTION (provided by applicant): Project Summary Meth-induced cognitive impairments observed in addicts after chronic drug use comprise a particularly serious problem in meth addiction and treatment. As such, there is a need for research efforts to develop animal models with translational relevance to the cognitive impairments observed in human meth addiction. Preclinical animal models reveal long-lasting impairments in recognition memory in rats. Specifically, high dose non-contingent meth injections can produce neurotoxicity and disrupt performance on memory tasks. Most object recognition studies have used short term, non-contingent drug delivery approaches to study the impact of meth on recognition memory. Intravenous meth self-administration offers a translational approach as a model of human meth addiction and the impact of chronic meth on cognitive function. The preliminary research shows that contingent long-access meth causes deficits in recognition memory, and that meth intake correlates with this memory deficit 24 hrs later. One purpose of this proposal is to determine whether these deficits in recognition memory involve a glutamatergic mechanism. In order to reverse meth-induced deficits in recognition memory, Specific Aim 1 will use a metabotropic glutamate receptor (mGluR) 2/3 agonist during acquisition of novel object recognition and Specific Aim 2 will use a mGluR5 positive allosteric modulator. Additionally, the experiments in this proposal will identify meth-induced changes in mGluR 2/3 and 5 expression in brain areas related to meth addiction (i.e., nucleus accumbens, dorsal striatum, and prefrontal cortex) and recognition memory (i.e., perirhinal cortex and hippocampus) following abstinence from long- access daily meth. Meth intake, object recognition scores, and receptor levels will be examined for correlations and predictive relationships. Identifying such relationships will provide new insights into meth- induced cognitive deficits, elucidate underlying neuronal mechanisms, and help identify possible therapeutic interventions in this animal model. PUBLIC HEALTH RELEVANCE: Project Narrative The overall purpose of these studies is to determine the relationships between motivated meth-taking behavior over time, meth-induced cognitive impairments, and the underlying neural mechanisms. The use of a translational animal model of meth addiction allows for the study of cognitive and motivational deficits that are manifested in meth addiction. Additionally, identification of neural mechanisms involved with this translational model may help identify promising new pharmacotherapeutic targets for meth-induced cognitive deficits.