DRUG ADDICTION: DUAL 5-HT INNERVATION OF LIMBIC SYSTEM

除了多巴胺（DA）的释放在奖赏中的作用外，最近的证据表明，丘脑核（NAc）中释放的5-HT可能有助于兴奋性药物的成瘾效应。 人们对5-HT投射到NAc的解剖组织知之甚少，需要这些数据来了解该系统的功能。 为了阐明5-HT神经元在成瘾和药物诱导的神经递质释放中的作用，本项目将分析5-HT投射到NAc和其他边缘系统结构的起源，并关注转运蛋白表达不同的5-HT轴突组。 许多精神兴奋剂药物通过单胺能转运体起作用，并且对前脑中5-HT和DA轴突的亚群具有不同的毒性。 为了确定调节兴奋剂药物药理学和毒性作用的因素，我们将研究5-HT和DA轴突对对氯苯丙胺（PCA）和甲基苯丙胺（Methh）的脆弱性。 我们已经确定了两种不同类型的5-HT轴突在NAc，其中之一密集支配的尾侧NAc壳，缺乏转运蛋白（SERT），是高度耐药。 还将分析前额叶（PFC）和内嗅皮层中类似的双重5-HT神经支配。(1)本项目将研究（a）支配NAc、PFC和内嗅皮质的5-HT轴突的神经元起源;（B）SERT mRNA和蛋白在起源细胞体中的表达;以及（c）相同的5-HT神经元是否将耐药轴突侧支发送到多个边缘靶区域。(2)将通过EM分析NAc壳和内嗅皮质，以确定这些区域是否接受具有新突触性质的静脉曲张5-HT轴突（缺乏SERT）的专门投射。 选择性5-HT神经毒素PCA将用于分离两种5-HT轴突类型以进行超微结构分析。 本研究为深入了解药物诱导5-HT释放的机制及5-HT在成瘾中的作用奠定了基础。 我们认为5-HT投射的双重性在成瘾、奖赏和情感状态控制中起着重要作用。 由脉冲传导引起的5-HT的自然生理释放不依赖于SERT，并且应该发生在所有5-HT轴突中，而药物诱导的释放需要转运蛋白并且更受限制。 因此，我们假设，生理兴奋的中缝神经元可能会产生不同的区域模式的5-HT释放比药物诱导的释放，差异可能是药物成瘾作用的基础。

In addition to the role of dopamine (DA) release in reward, recent evidence suggests that 5-HT released in the nucleus accumbens (NAc) may contribute to the addictive effects of stimulant drugs. Little is known about the anatomic organization of 5-HT projections to the NAc and such data are needed to understand the function of this system. In order to elucidate the role of 5-HT neurons in addiction and in drug- induced release of neuro-transmitter, this project will analyze the origin of 5-HT projections to the NAc and to other limbic structures with attention to sets of 5-HT axons that differ in transporter expression. Many psychostimulant drugs act via monoaminergic transporters and are differentially toxic to subsets of 5-HT and DA axons in forebrain. To identify factors that mediate the pharmacologic and toxic effects of stimulant drugs, we will study the vulnerability of 5-HT and DA axons to p- chloroamphetamine (PCA) and to methamphetamine (Meth). We have identified two separate types of 5-HT axons in the NAc, one of which densely innervates the caudal NAc shell, lacks the transporter (SERT) and is highly drug-resistant. A similar dual 5-HT innervation in prefrontal (PFC) and in entorhinal cortex will also be analyzed. (1) This project will investigate (a) the neuronal origins of 5-HT axons that innervate NAc, PFC and entorhinal cortex; (b) the expression of SERT mRNA and protein in the cell bodies of origin; and (c) whether the same 5-HT neurons send drug-resistant axon collaterals to multiple limbic target areas. (2) The NAc shell and entorhinal cortex will be analyzed by EM to establish whether these regions receive a specialized projection of varicose 5-HT axons (lacking SERT) with novel synaptic properties. The selective 5-HT neurotoxin, PCA, will be used to separate the two 5-HT axon types for ultrastructural analysis. This study should contribute to understanding the mechanisms of drug-induced 5-HT release and the role of 5-HT in addiction. We propose that the duality of 5-HT projections plays an important role in addiction, reward and affective state control. Natural, physiologic release of 5-HT resulting from impulse conduction is independent of SERT and should occur in all 5-HT axons, whereas drug-induced release requires the transporter and is more restricted. Therefore, we postulate that physiologic excitation of raphe neurons is likely to produce a different regional pattern of 5-HT release than does drug-induced release, a difference that may underlie the addictive effects of drugs.