Cocaine Addiction and the Role of Serotonin in Orbitofrontal Cortex Function

利用脑切片全细胞电生理学，我们发现在停止可卡因自我给药（CSA）或联合给药（CYA）后，锥体神经元（PyNs）中5-HT1A和5-HT2A受体激活的生理效应显著降低。此外，在可卡因戒断后，5-羟色胺对这些受体的减弱作用持续了数周，这表明它们可能与可卡因成瘾的长期方面有关，例如毒品渴望。由于OFC中的5-羟色胺与行为灵活性、学习和其他认知能力有关，我们的实验为5-羟色胺在可卡因成瘾以及可卡因成瘾和戒断过程中表现出的决策障碍中所起的作用提供了新的信息。此外，由于5-HT与多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），这些实验为OFC中靶向5-HT系统作为潜在治疗方法的临床应用提供了有价值的信息。

Using whole-cell electrophysiology in brain slices, we find that physiological effects of 5-HT1A and 5-HT2A receptor activation were dramatically reduced following withdrawal of either cocaine self-administration (CSA) or yoked cocaine administration (CYA) in pyramidal neurons (PyNs). Moreover, these reduced effects of 5-HT at these receptors persisted for many weeks after cocaine withdrawal, suggesting they may be involved in long-term aspects of cocaine addiction, such as drug craving. As 5-HT in the OFC is implicated in behavioral flexibility, learning and other cognitive abilities, our experiments 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 stress disorder (PTSD), these experiments provide valuable information as to the clinical utility of targeting the 5-HT system in the OFC as potential therapies. Our recent efforts in this project have focused on developing a transgenic rat model that will permit us to examine the role of 5-HT in the regulation of a class of important neurons in the OFC, known as fast-spiking (FS), parvalbumin (PV), interneurons. These neurons constitute a minority of the total cell population in the OFC, but are important because they use the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), to coordinate the activity of the much larger population of pyramidal neurons, via extensive synaptic connections. Therefore, these neurons are integral to the computational processes that are necessary for normal OFC function, and are likely to be involved in psychiatric and addiction disorders in which this brain are contributes. To study these neurons our transgenic core and scientific collaborators have developed a rat model in which the PV gene promoter drives the expression of cre recombinase. This permits selective expression fluorescent proteins and opsins, such as channelrhodopsin-2 (ChR2), that allows us to study these neurons, and manipulate their activity with light. Our most recent studies indicate that 5-HT signaling, although present in PV cells in the OFC, is not altered after withdrawal from cocaine self-administration. Therefore, the changes in 5-HT function related to cocaine exposure appear to be mediated almost entirely by pyramidal neurons in the OFC. Moreover, in this latter study we examined changes in OFC parvalbumin cells between male and female rats. We found that female OFC parvalbumin cells receive weaker glutamatergic synaptic inputs than males and that these synaptic currents are reduced following 5 weeks of withdrawal from cocaine self-administration only in males. Additionally, parvalbumin cells from male rats were also depolarized after cocaine withdrawal. Pharmacological studies have also shown that the excitation of parvalbumin neurons by 5-HT in the OFC can be blocked by a non-selective antagonist of 5-HT2A/C receptors, known as ketanserin, only in neurons from female rats. To gain additional insight as to whether this indicates a distinct functional expression of 5-HT2A or 5HT2C receptors in parvalbumin neurons between males and females, we are conduction additional studies using more selective antagonists of these receptors, along with a a 5-HT2 receptor-selective agonist, known as DOI. Our data suggest that there are sex-linked differences in the functional properties of parvalbumin neurons in the OFC after cocaine withdrawal, and that these changes could explain differential vulnerabilities to cocaine addiction and psychiatric sequalae in humans. It is hoped that the identification of the roles of these neurons in psychiatric illness and addiction will aid in developing novel targeted therapeutic approaches for treatment in humans.