Reversal of Methamphetamine Induced Cognitive Deficits and mGlu Receptors

逆转甲基苯丙胺引起的认知缺陷和 mGlu 受体

• 批准号: 8077331
• 负责人: Carmela M Reichel
• 金额: $ 1.53万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077331
• 关键词: Abstinence; Agonist; Amphetamines; Animal Model; Area; Attenuated; Behavior; Brain; Chronic; Cocaine; Cognitive; Cognitive deficits; Corpus striatum structure; Cues; Dorsal; Dose; Drug Delivery Systems; Drug usage; Glutamates; Goals; Hippocampus (Brain); Human; Impaired cognition; Impairment; Injection of therapeutic agent; Intake; Intravenous; Laboratories; Memory; Memory impairment; Metabotropic Glutamate Receptors; Methamphetamine; Methamphetamine dependence; Modeling; Neurons; Nucleus Accumbens; Pathology; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phase; Prefrontal Cortex; Public Health; Rattus; Receptor Activation; Reporting; Research; Reversal Learning; Saline; Self Administration; Testing; Therapeutic Intervention; Time; cognitive function; experience; insight; learning extinction; meetings; memory recognition; metabotropic glutamate receptor 2; methamphetamine abuse; neuromechanism; neurotoxicity; novel; object recognition; pre-clinical; psychostimulant; public health relevance; receptor; receptor expression; research study; translational approach

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.

描述（由申请人提供）： 项目摘要 长期吸毒后在成瘾者中观察到的冰毒引起的认知障碍是冰毒成瘾和治疗中一个特别严重的问题。因此，需要进行研究工作来开发与人类冰毒成瘾中观察到的认知障碍具有转化相关性的动物模型。临床前动物模型揭示了大鼠认知记忆的长期损害。具体来说，高剂量的非偶然冰毒注射会产生神经毒性并扰乱记忆任务的表现。大多数物体识别研究都使用短期、非偶然的药物输送方法来研究冰毒对识别记忆的影响。静脉注射冰毒自我给药提供了一种转化方法，作为人类冰毒成瘾模型以及慢性冰毒对认知功能的影响。初步研究表明，长期服用冰毒会导致识别记忆缺陷，而冰毒摄入量与 24 小时后的记忆缺陷相关。该提案的一个目的是确定这些识别记忆缺陷是否涉及谷氨酸能机制。为了扭转冰毒引起的识别记忆缺陷，Specific Aim 1 将在获得新物体识别过程中使用代谢型谷氨酸受体 (mGluR) 2/3 激动剂，Specific Aim 2 将使用 mGluR5 正变构调节剂。此外，本提案中的实验将确定在戒除长期服用冰毒后，与冰毒成瘾（即伏核、背侧纹状体和前额皮质）和识别记忆（即鼻周皮层和海马）相关的大脑区域中冰毒引起的 mGluR 2/3 和 5 表达的变化。将检查冰毒摄入量、物体识别分数和受体水平的相关性和预测关系。确定这种关系将为了解冰毒引起的认知缺陷提供新的见解，阐明潜在的神经元机制，并帮助确定该动物模型中可能的治疗干预措施。 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，动机性吸食冰毒行为、冰毒引起的认知障碍和潜在的神经机制之间的关系。使用冰毒成瘾的转化动物模型可以研究冰毒成瘾中表现的认知和动机缺陷。此外，识别与这种转化模型相关的神经机制可能有助于确定治疗冰毒引起的认知缺陷的有希望的新药物治疗靶点。