Cocaine Addiction and the Role of Serotonin in Orbitofrontal Cortex Function

在过去的一年里，我们成功地记录了从大鼠脑片中获得的OFC神经元，并检测了5-羟色胺(5-HT)对这些神经元的影响。此外，我们已经证实，在接受自我注射可卡因的训练的大鼠中，基线谷氨酸介导的突触传递存在缺陷，这种训练结束后可持续许多个月。这种OFC突触传递的缺陷与巴甫洛夫式过度期望行为任务的表现下降有关，该任务被认为依赖于完整的OFC功能。我们还发现，逆转这一缺陷可以恢复出乎意料的行为，支持OFC中突触功能改变是可卡因成瘾的主要结果的假设，这可能会导致决策能力受损，甚至更广泛的认知。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，以及可卡因经验如何改变这种活动。这些实验将提供新的信息，关于5-羟色胺在可卡因成瘾中所起的作用，以及在可卡因成瘾和戒断过程中表现出的决策障碍。此外，由于5-羟色胺与几种神经精神障碍有关，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)，这些实验应该提供有价值的信息，说明将5-羟色胺系统作为潜在治疗方法在OFC中的临床应用。

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.