Cocaine Addiction and the Role of Serotonin in Orbitofrontal Cortex Function

可卡因成瘾和血清素在眶额皮层功能中的作用

• 批准号: 8933873
• 负责人: Carl R. Lupica
• 金额: $ 17.64万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8933873
• 关键词: Affect; Aggressive behavior; Amygdaloid structure; Animals; Anxiety; Area; Behavior; Behavioral; Brain; Cells; Clinical; Cocaine; Cocaine Dependence; Cognition; Cognitive; Data; Decision Making; Dementia; Disease; Drug Addiction; Exhibits; Functional disorder; Glutamates; Human; Impairment; Infusion procedures; Interneurons; Lead; Lesion; Limbic System; Link; Medial Dorsal Nucleus; Mediating; Mental Depression; Metabolic; Modality; Modeling; Moths; Neuromodulator; Neurons; Neurotransmitters; Obsessive-Compulsive Disorder; Outcome; Output; Performance; Physiological; Play; Positioning Attribute; Process; Pyramidal Cells; Rattus; Reporting; Reversal Learning; Rewards; Role; Self Administration; Self-Administered; Sensory; Serotonin; Serotonin Agents; Serotonin Receptor 5-HT2C; Slice; Smell Perception; Synapses; Synaptic Transmission; System; Taste Perception; Training; Ventral Striatum; Vision; Visual; Withdrawal; addiction; base; classical conditioning; cocaine exposure; dorsal raphe nucleus; experience; extracellular; hippocampal pyramidal neuron; nerve supply; neuropsychiatry; novel; primary outcome; raphe nuclei; receptor; reinforcer; research study; synaptic function

During the past fiscal year we have successfully recorded from OFC neurons in brain slices obtained from rats, and have examined the effects of serotonin (5-HT) on these neurons. In addition, we have established that there is a deficit in baseline glutamate-mediated synaptic transmission in rats trained to self-administer cocaine that lasts for many moths after this training is finished. This deficit in OFC synaptic transmission was associated with decreased performance in a Pavlovian overexpectation behavioral task that is known to be reliant upon intact OFC function. We also found that reversing this deficit could restore the overexpectatio behavior, supporting the hypothesis that altered synaptic function in the OFC is a primary outcome of cocaine addiction, that may lead to impaired decision making, and more generally cognition. Current studies are now focused upon the potential role that 5-HT plays in regulating OFC neuron activity, and whther cocaine experience alters this activity. These experiments will provide novel information as to the role that 5-HT plays in cocaine addiction, and in the impaired decision-making exhibited during cocaine addiction and withdrawal. In addition, since 5-HT is linked to several neuropsychiatric disorders, such as depression, anxiety, dementia, impulsive-aggression disorder (IAD), obsessive-compulsive disorder (OCD), and post-traumatic stres disorder (PTSD), these experiments should provide valuable information as to the clinical utility of targeting the 5-HT system in the OFC as potential therapies.

在过去的财政年度中，我们在从大鼠获得的大脑切片中成功记录了OFC神经元，并检查了5-羟色胺（5-HT）对这些神经元的影响。 此外，我们已经确定，基线谷氨酸介导的突触传播缺乏，该大鼠受过训练的自我管理可卡因的大鼠，在这项训练完成后持续许多飞蛾。 OFC突触传播中的这种赤字与Pavlovian过度期望的行为任务的性能降低有关，该任务已知依赖于完整的OFC函数。 我们还发现，逆转这种赤字可以恢复过度的行为，支持以下假设：OFC中改变突触功能是可卡因成瘾的主要结果，这可能导致决策受损，并且更普遍地认知。 现在，目前的研究集中在5-HT在调节C神经元活性的潜在作用上，可卡因经历改变了这一活性。 这些实验将提供有关5-HT在可卡因成瘾中扮演的作用以及在可卡因成瘾和戒断期间表现出的决策受损的新信息。 此外，由于5-HT与几种神经精神疾病有关，例如抑郁症，焦虑，痴呆，脉冲 - 肌肉攻击障碍（IAD），强迫症（OCD）和创伤后Stres障碍（PTSD），这些实验应为针对5-HT的临床系统提供潜在的实验性信息。