Cocaine, Opoids and Drug Abuse

可卡因、阿片类药物和药物滥用

• 批准号: 8452216
• 负责人: Peter W Kalivas
• 金额: $ 7.08万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452216
• 关键词: Abbreviations; Acetylcysteine; Adaptive Behaviors; Agonist; Animal Model; Award; Behavioral; Binding; Biochemical; Brain; Catalytic Domain; Cerebrospinal Fluid; Characteristics; Chemosensitization; Chronic; Cocaine; Cocaine Dependence; Corpus striatum structure; Cysteine; Cystine; Dendritic Spines; Dependovirus; Dose; Drug abuse; Electric Stimulation; Equilibrium; Excitatory Postsynaptic Potentials; Extinction (Psychology); Frequencies; Funding; GTP-Binding Proteins; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Homeostasis; Impairment; Laboratories; Measurement; Measures; Mental Depression; Metabotropic Glutamate Receptors; Modeling; Morphology; N-Methylaspartate; Neuronal Plasticity; Neurons; Nucleus Accumbens; Output; Pharmacological Treatment; Prefrontal Cortex; RNA; Rattus; Regulation; Relapse; Research; Role; Signal Transduction; Slice; Small Interfering RNA; Surface; Synapses; Synaptic plasticity; System; Tissues; addiction; behavioral sensitization; extracellular; human RASD1 protein; in vivo; metabotropic glutamate receptor 2; nerve supply; neuroadaptation; postsynaptic; presynaptic; public health relevance; repaired; research study; response; restoration; synergism; transmission process; uptake

DESCRIPTION (provided by applicant): This a 10-year competitive renewal of a Merit Award that builds upon a total of 25 years of previously funded research. Over this period we have identified the role of glutamate transmission in the nucleus accumbens as critical for behavioral sensitization and the reinstatement of cocaine seeking in an animal model of relapse. Both pre- and postsynaptic cocaine-induced neuroadaptations have been discovered. Recently, the diverse array of cocaine induced changes discovered in our laboratory and by others have been amalgamated into the glutamate homeostasis hypothesis of addiction wherein dysregulation in the balance between synaptic and nonsynaptic glutamate release and uptake is proposed to be critical in the vulnerability to relapse. Supporting this hypothesis, restoring glutamate homeostasis with N-acetylcysteine (NAC) has been shown to produce enduring protection against reinstated cocaine seeking, and appears to normalize many cocaine-induced changes in synaptic plasticity. In the aim #1 of the present proposal we will further characterize the behavioral protection by NAC, evaluating dose-response curves and duration of action after discontinuing NAC. The remaining 3 aims focus on our recent findings that NAC produces an enduring restoration in measures of glutamate homeostasis and metabotropic glutamate receptor (mGluR) dependent neuroplasticity in the nucleus accumbens. Accordingly, aim #2 evaluates the enduring restoration by NAC in the level and function of nonsynaptic glutamate release via the cystine-glutamate exchanger and glial glutamate uptake. Aim #3 determines if daily NAC restores classic measures of neuroplasticity, including longterm potentiation, longterm depression and dendritic spine morphology. Finally, aim #4 examines the effects of daily NAC on signaling via presynaptic mGluR2/3 and postsynaptic signaling on mGluR5. Moreover, in this aim it will be determined if mGluR agonists and antagonists can promote or inhibit the capacity of daily NAC to normalize glutamate homeostasis and synaptic plasticity in the nucleus accumbens. PUBLIC HEALTH RELEVANCE: Cocaine addiction is associated with impaired neuroplasticity in the prefrontal cortico-striatal brain circuitry that is important for guiding adaptive behavior. The premise of this proposal is that it is possible to repair this corticostriatal deficit and thereby ameliorate the vulnerability to relapse. Accordingly, we propose to characterize the ability of daily N-acetylcysteine treatment to produce enduring protection from the reinstatement of cocaine seeking, and associate this protection with restoring neuroplasticity.

描述（由申请人提供）：这是为期10年的竞争性裁员，以绩效奖励为基于总计25年的先前资助研究。在此期间，我们已经确定谷氨酸传播在伏伏核中的作用对于行为敏化和恢复可卡因在动物复发模型中寻求的作用至关重要。已经发现了突触前可卡因诱导的神经加热。最近，在我们的实验室和其他人中发现的各种可卡因诱发的变化已被合并为成瘾的谷氨酸稳态假说，其中建议突触和非突触性谷氨酸释放和摄取之间的平衡失调对于易于复活的脆弱性至关重要。支持这一假设，已证明，用N-乙酰半胱氨酸（NAC）恢复谷氨酸稳态可以产生持久的可卡因寻求可卡因，并且似乎使许多可卡因诱导的突触可塑性变化正常化。 在本提案的目标＃1中，我们将通过NAC进一步表征NAC的行为保护，评估剂量反应曲线和中断NAC后的作用持续时间。 其余的3个目的是我们最近的发现，即NAC在谷氨酸稳态和代谢性谷氨酸受体（MGLUR）依赖性神经塑性中产生持久的恢复。因此，AIM＃2评估了NAC在非突触谷氨酸释放的水平和功能中通过胱氨酸 - 谷氨酸交换剂和神经胶质谷氨酸摄取的持久恢复。 AIM＃3确定每日NAC是否恢复了神经可塑性的经典度量，包括长期增强，长期抑郁和树突状脊柱形态。最后，AIM＃4通过突触前MGLUR2/3和突触后信号对MGLUR5进行了每日NAC对信号传导的影响。此外，在此目的中，将确定MGLUR激动剂和拮抗剂是否可以促进或抑制NAC在伏隔核中每天NAC归一化和突触可塑性正常化的能力。 公共卫生相关性：可卡因成瘾与前额叶皮质 - 纹状体脑电路的神经可塑性受损有关，这对于指导适应性行为很重要。该提议的前提是可以修复这种皮质纹状体赤字，从而改善复发的脆弱性。 因此，我们建议表征每日N-乙酰半胱氨酸治疗产生持久保护免受可卡因寻求恢复的能力，并将这种保护与恢复神经可塑性相关联。