Synaptic Transmission: Modulation, Plasticity And Effects Of Drugs Of Abuse

突触传递：调节、可塑性和滥用药物的影响

• 批准号: 9155443
• 负责人: David M Lovinger
• 金额: $ 110.13万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 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/9155443
• 关键词: Acute; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcoholic Intoxication; Alcohols; Behavior; Behavior Control; Brain; Brain region; CNR1 gene; Catabolism; Chronic; Clinical Research; Cocaine; Cognition; Corpus striatum structure; Coupled; Decision Making; Dependence; Dopamine; Dorsal; Dose; Drug Exposure; Drug effect disorder; Elements; Endocannabinoids; Ethanol; Exposure to; G-Protein-Coupled Receptors; GTP-Binding Proteins; Glutamates; Goals; Green Fluorescent Proteins; Habits; Interneurons; Intoxication; Investigation; Laboratories; Learning; Lobular Neoplasia; Long-Term Depression; Measures; Mediating; Membrane Proteins; Motivation; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neurophysiology - biologic function; Neurosciences; Opioid Receptor; Oxycodone; Pattern; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Population; Prefrontal Cortex; Probability; Process; Prosencephalon; Psychological reinforcement; Rattus; Receptor Activation; Recruitment Activity; Reporter; Reporting; Research; Research Personnel; Rewards; Role; Scanning; Sensorimotor functions; Signal Transduction; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Thalamic structure; Training; Ventral Striatum; Work; addiction; alcohol and other drug; alcohol behavior; alcohol effect; alcohol exposure; alcohol seeking behavior; base; cholinergic; dopaminergic neuron; drinking; drug of abuse; in vivo; interest; metabotropic glutamate receptor 2; nerve supply; neural circuit; neuroadaptation; neurogenetics; neuronal circuitry; neuroregulation; optogenetics; prescription opiate; prevent; protein expression; psychostimulant; receptor; receptor function; relating to nervous system; research study; response; striosome; synaptic depression; translational study

Research within the Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, continues to focus on mechanisms underlying neuromodulation and plasticity and the effects of alcohol and other drugs of abuse on these neuronal functions. Our main interest is the function of the dorsal striatum (DS), a brain region involved in action control and selection, as well as action learning and addiction. Striatal Synaptic Plasticity and Drugs of Abuse We have continued our examination of changes in long-lasting striatal synaptic plasticity following in vivo exposure to drugs of abuse. These studies are carried out with electrophysiological recording in brain slices following the in vivo treatment. Our previous findings indicated that exposure to ethanol for 2-4 weeks in vivo led to a decrease in a form of long-term synaptic depression (LTD) that is initiated by endogenous cannabinoid (endocannabinoid) activation of CB1 receptors on cortical afferents to the dorsolateral striatum (DLS). In addition to CB1 receptors that activate Gi/o-type G-proteins, LTD at corticostriatal synapses can also be induced by activation of other G protein-coupled receptors (GPCRs) that activate Gi/o-dependent intracellular signaling. It appears that these forms of LTD are expressed presynaptically as a decrease in the probability of glutamate release. The mu opiate receptor (MOR) is among the receptors that can trigger LTD, and we recently reported that MOR-LTD is prevented by prior in vivo exposure to even a single dose of the prescription opiate drug oxycodone. The LTD activated by delta-type opiate receptors (DORs) is not affected by this in vivo drug exposure. Interestingly, MOR-LTD is mutually occlusive with endocannabinoid-LTD, while no such interactions between DOR-LTD and either endocannabinoid- or MOR-LTD are observed. Thus, it appears that DOR-LTD occurs at a separate synaptic population or has a mechanism distinct from MOR- and endocannabinoid-LTD. Preliminary experiments indicate that chronic intermittent ethanol exposure prevents MOR-LTD, while DOR-LTD is unaffected by this exposure. Our current working hypothesis is that chronic exposure to several drugs of abuse results in loss of some forms of Gi/o-mediated LTD in DLS. Loss of this synaptic depression would result in stronger cortical drive onto the projection neurons of the DLS. Given the role of the DLS in habit formation, the net effect of these drug actions on LTD could be the promotion of habitual drug seeking and taking. We have worked with the Laboratory of Neurogenetics and the Laboratory of Clinical and Translational Studies here at NIAAA to examine another form of corticostriatal LTD initiated by activation of the Gi/o-coupled metabotropic glutamate receptor 2 (mGluR2 or GRIM2). This receptor and the LTD resulting from its activation are missing in the alcohol preferring P rats. Mice lacking the receptor show increased alcohol intake, implicating GRIM2 in control of drinking. We are currently examining if the function of this receptor is altered following chronic alcohol exposure, and how the receptor might contribute to excess drinking. We are also using optogenetic techniques to examine synapses in the striatum made by afferents from identified cortical and thalamic regions. This analysis will allow us to determine what forms of Gi/o-mediated LTD occur at which synapses both under control conditions and following in vivo drug exposure. Dopamine Release and Modulation Thereof in Different Striatal Subcompartments The striatum can be separated into striosome and matrix subcompartments based on protein expression patterns, afferent innervation and efferent projection targets. Within the dorsal striatum, and especially in DLS, the striosome compartments/continuum generally processes associative and/or limbic information, while the larger matrix handles sensorimotor functions. We have used a mouse that expresses green fluorescent protein preferentially in the striosome compartment, as characterized in LIN (the Nr4a1-GFP mouse) to examine subcompartmental differences in control of dopamine. Dopamine has key roles in controlling striatal circuitry, and as such has been implicated in action control, decision making, motivation, reward and reinforcement. We used fast-scan cyclic voltammetry to measure dopamine release in the different subcompartments in striatal slices from these reporter mice. In the dorsal striatum, dopamine release was stronger in matrix than in striosomes, while the opposite was true in more ventral striatal regions. Cocaine enhanced dopamine release to a greater extent in striosomes than in matrix in the dorsal striatum. These findings indicate that dopaminergic influence may initially be weaker in striosomes, perhaps due to high levels of expression of the dopamine clearing transporter. Psychostimulant drugs that act through this transporter appear to equalize release in the two subcompartments, perhaps leading to increased associative/limbic circuitry influences on the dorsal striatum. We have also examined modulation of dopamine release by CB1 agonists and endocannabinoids in the ventral striatum. We find that CB1 receptor activation inhibits dopamine release when release is driven by optogenetic activation of striatal cholinergic interneurons (CINs). This modulation was observed either with synthetic CB1 agonists or when endocannabinoid levels were enhanced by blocking catabolism or by short trains of CIN activation. The release driven by CINs is also inhibited when glutamatergic synaptic transmission is inhibited, and the effects of CB1 activation and glutamatergic antagonism are mutually occlusive. Dopaminergic neurons and CINs do not express CB1, and this CB1 modulation was prevented when receptors were removed from prefrontal cortex afferents to ventral striatum. Thus, our evidence supports the idea that CIN activation recruits cortical glutamatergic afferents that help to drive dopamine release. This cortical glutamatergic drive is itself modulated by endocannabinoids acting through CB1 receptors. These findings provide evidence of a new mechanism for control of dopamine and its many neural functions.

关于综合神经科学实验室的研究，关于突触药理学的部分，继续专注于神经调节和可塑性的基础机制以及酒精和其他滥用药物对这些神经元功能的影响。我们的主要兴趣是背纹状体（DS）的功能，这是一个涉及动作控制和选择的大脑区域，以及动作学习和成瘾。 纹状体突触可塑性和滥用药物 在体内暴露于滥用药物后，我们一直在检查长期纹状体突触可塑性的变化。 这些研究是在体内治疗后用电生理记录在脑切片中进行的。我们先前的发现表明，体内接触2-4周的乙醇导致长期突触抑郁症（LTD）的降低，该形式是由内源性大麻素（内源性大麻素（内源性大麻素）激活）激活CB1受体对皮质传入的层状脂肪酸（DLS）的激活。 除了激活GI/O-Type G蛋白的CB1受体外，在皮质纹状体突触中的LTD还可以通过激活其他G蛋白偶联受体（GPCR）来诱导，从而激活GI/O依赖性细胞内信号传导。 看来这些形式的有限公司在突触前表达，这是谷氨酸释放概率的降低。 MU鸦片受体（MOR）是可以触发LTD的受体之一，我们最近报告说，通过体内接触到即使是单一剂量的Operiate Opiate药物羟考酮，也可以预防MOR-LTD。 由Delta型阿片受体（DOR）激活的LTD不受这种体内药物暴露的影响。 有趣的是，MOR-LTD与内源性大麻素LTD相互遮住，而DOR-LTD与内源性大麻素或MOR-LTD之间没有这种相互作用。 因此，似乎DOR-LTD发生在单独的突触群体上，或具有与MOR-和内源性大麻素-LTD不同的机制。 初步实验表明，慢性间歇性乙醇暴露可防止MOR-LTD，而DOR-LTD不受这种暴露影响。 我们目前的工作假设是，长期暴露于几种滥用药物会导致DLS中某些形式的GI/O介导的LTD丧失。 这种突触抑制的丧失将导致对DLS投射神经元的皮质驱动更强。 鉴于DLS在习惯形成中的作用，这些药物作用对LTD的净影响可能是促进习惯性药物寻求和服用。 我们曾与NIAAA的神经遗传学实验室和临床和转化研究实验室合作，研究了通过激活GI/O偶联的代谢型谷氨酸受体2（MGLUR2或GRIM2）激活的另一种形式的皮质纹状体LTD。 该受体和由其激活引起的LTD在酒精中偏爱P大鼠中缺少。 缺乏受体的小鼠表明酒精摄入量增加，这意味着Grim2在控制饮酒方面。 目前，我们正在研究该受体的功能是否在慢性酒精暴露后是否会改变，以及受体如何导致过量饮酒。 我们还使用光遗传技术来检查来自已鉴定的皮质和丘脑区域传入的纹状体中的突触。 该分析将使我们能够确定发生了哪种形式的GI/O介导的LTD，在对照条件下和体内药物暴露后都会突触。 多巴胺释放及其在不同纹状体子组门中的调制 基于蛋白质表达模式，传入神经和传出的投影靶标，纹状体可以分为静脉曲箱和基质子组门。 在背纹状体，尤其是在DLS中，striosome隔室/连续体通常会处理关联和/或边缘信息，而较大的矩阵则处理感觉运动功能。 我们已经使用了一只小鼠在striosome室中优先表达绿色荧光蛋白的小鼠，如Lin（NR4A1-GFP小鼠）中的特征，以检查多巴胺控制中各个小节差异。 多巴胺在控制纹状体电路中具有关键作用，因此与动作控制，决策，动机，奖励和增强有关。 我们使用快速扫描的循环伏安法来测量这些记者小鼠的纹状体切片中不同子部门中的多巴胺释放。 在背纹状体中，基质中的多巴胺释放比在脊髓膜中更强，而在更腹侧的纹状体区域中相反。 可卡因增强了多巴胺在脊髓膜中的释放，而不是背纹状体中的基质。 这些发现表明，多巴胺能的影响最初可能是由于多巴胺清除转运蛋白的高表达而导致的。 通过该转运蛋白起作用的精神刺激药物似乎在两个子部门的释放中均等，可能导致缔合/边缘电路对背纹状体的影响增加。 我们还研究了CB1激动剂和腹侧纹状体内源性大麻素对多巴胺释放的调节。 我们发现，当释放是由纹状体胆碱能中间神经元（CIN）释放驱动时，CB1受体激活抑制了多巴胺的释放。 使用合成CB1激动剂观察到这种调节，或者通过阻断分解代谢或通过短列CIN激活来增强内源性大麻素水平时。 当抑制谷氨酸能突触传播时，也抑制了CINS驱动的释放，并且CB1激活和谷氨酸能拮抗作用的作用是相互闭塞的。 多巴胺能神经元和CIN不表达CB1，当将受体从前额叶皮层传入到腹侧纹状体中时，可以防止这种CB1调节。 因此，我们的证据支持CIN激活募集有助于驱动多巴胺释放的皮质谷氨酸能传入的观念。 这种皮质谷氨酸能驱动本身是由通过CB1受体作用的内源性大麻素调节的。这些发现提供了控制多巴胺及其许多神经功能的新机制的证据。