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.

在过去的财政年度里，我们成功地记录了大鼠脑切片中的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，在训练自我使用可卡因的大鼠中，基线谷氨酸介导的突触传递存在缺陷，这种缺陷在训练结束后持续数月。OFC突触传递的缺陷与巴甫洛夫过度期望行为任务的表现下降有关，而这种任务依赖于完整的OFC功能。我们还发现，逆转这种缺陷可以恢复过度预期行为，支持了OFC突触功能改变是可卡因成瘾的主要结果的假设，这可能导致决策和更普遍的认知受损。目前的研究集中在5-羟色胺在调节OFC神经元活动中的潜在作用，以及可卡因是否会改变这种活动。这些实验将为5-羟色胺在可卡因成瘾中的作用以及在可卡因成瘾和戒断过程中表现出的决策障碍提供新的信息。此外，由于5-HT与几种神经精神疾病有关，如抑郁、焦虑、痴呆、冲动攻击障碍（IAD）、强迫症（OCD）和创伤后应激障碍（PTSD），这些实验应该为OFC中靶向5-HT系统作为潜在治疗方法的临床应用提供有价值的信息。