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

基本信息

批准号：
8941389
负责人：
David M Lovinger
金额：
$ 135.47万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
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/8941389
关键词：
Acute Agonist Alcohol consumption Alcohol dependence Alcoholic Intoxication Alcohols Behavior Behavior Control Brain Brain region Cannabinoids Catabolism Chronic Cognition Collaborations Corpus striatum structure Decision Making Dependence Dorsal Drug Exposure Drug effect disorder Elements Ethanol Exposure to G-Protein-Coupled Receptors Genes Genetic Polymorphism Glutamates Goals Habits Impairment Injection of therapeutic agent Intoxication Investigation Laboratories Learning Lobular Neoplasia Long-Term Depression Mediating Membrane Proteins Mus National Institute on Alcohol Abuse and Alcoholism Neurons Neurosciences Nonsense Codon Opioid Opioid Peptide Opioid Receptor Oxycodone Pharmaceutical Preparations Pharmacology Phenotype Physiological Play Population Presynaptic Receptors Probability Process Prosencephalon Rattus Research Research Personnel Role Serotonin Site Synapses Synaptic Transmission Synaptic plasticity addiction alcohol and other drug alcohol behavior alcohol effect alcohol seeking behavior base cannabinoid receptor delta opioid receptor drug of abuse endogenous opioids in vivo interest kappa opioid receptors loss of function metabotropic glutamate receptor 2 mu opioid receptors neural circuit neuroadaptation neuroregulation preference presynaptic receptor receptor function relating to nervous system response synaptic depression

Acute Agonist Alcohol consumption Alcohol dependence Alcoholic Intoxication Alcohols Behavior Behavior Control Brain Brain region Cannabinoids Catabolism Chronic Cognition Collaborations Corpus striatum structure Decision Making Dependence Dorsal Drug Exposure Drug effect disorder Elements Ethanol Exposure to G-Protein-Coupled Receptors Genes Genetic Polymorphism Glutamates Goals Habits Impairment Injection of therapeutic agent Intoxication Investigation Laboratories Learning Lobular Neoplasia Long-Term Depression Mediating Membrane Proteins Mus National Institute on Alcohol Abuse and Alcoholism Neurons Neurosciences Nonsense Codon Opioid Opioid Peptide Opioid Receptor Oxycodone Pharmaceutical Preparations Pharmacology Phenotype Physiological Play Population Presynaptic Receptors Probability Process Prosencephalon Rattus Research Research Personnel Role Serotonin Site Synapses Synaptic Transmission Synaptic plasticity addiction alcohol and other drug alcohol behavior alcohol effect alcohol seeking behavior base cannabinoid receptor delta opioid receptor drug of abuse endogenous opioids in vivo interest kappa opioid receptors loss of function metabotropic glutamate receptor 2 mu opioid receptors neural circuit neuroadaptation neuroregulation preference presynaptic receptor receptor function relating to nervous system response synaptic depression

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项目摘要

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. Striatal Synaptic Plasticity and Effects of Drugs of Abuse We have examined many forms of synaptic plasticity at synapses within the DS. One of the most prominent is long-term depression (LTD) at glutamatergic corticostriatal synapses produced via activation of the Gi/o class of G-protein-coupled receptors (GPCRs). In addition to LTD induced by activation of cannabinoid type 1 (CB1) and serotonin type 1B receptors, we have also observed that activation of the mu, delta and kappa receptors for opioid peptides can induce LTD. Likewise, inhibition of opioid peptide catabolism induces LTD, and this synaptic depression appears to involve actions of endogenous opioid peptides at the three receptor subtypes. The expression of the LTD induced by mu and delta opioid receptors involves decreased probability of glutamate release, resembling the mechanism of CB1-dependent LTD. Indeed, mu opioid receptor and CB1-dependent LTD can occlude on another, indicating that they share mechanisms at an overlapping population of synapses. In contrast, delta opioid receptor-dependent LTD cannot be occluded by mu-dependent LTD, indicating separate sites of action for these two opioid-mediated forms of synaptic plasticity. We have examined effects on striatal LTD of in vivo exposure to the widely-prescribed and heavily abused opioid receptor agonist oxycodone as well as ethanol. A single injection of oxycodone in vivo leads to loss of mu- and CB1-dependent LTD. The effects persist for up to 4 days following a single drug injection. The in vivo oxycodone injection has no effect on delta receptor-mediated LTD. Similar loss of mu- and CB1-dependent forms of LTD is observed following 2-4 weeks of in vivo exposure to intoxicating concentrations of ethanol. Thus, impairment of certain forms of presynaptic LTD appears to be a common impairment produced by different drugs of abuse. Loss of LTD likely alters cortical control of striatal medium spiny neurons, perhaps contributing to alterations in striatal-dependent learning produced by drugs such as ethanol, and perhaps contributing to habitual drug seeking. It will be important to figure out how mechanisms involved in LTD are impaired by in vivo drug exposure. The metabotropic glutamate receptor 2 (mGluR2) is another presynaptic receptor implicated in modulation and long-term depression of corticostriatal glutamatergic synpases. In collaboration with the laboratories of Drs. David Goldman and Markus Heilig here at NIAAA we have confirmed that a polymorphism that produces a premature stop codon in this gene (the grm2 gene) leads to loss of function of this receptor in alcohol-preferring (P) rats. Presynaptic receptor function is completely lost at corticostriatal synapses. Studies performed by the Goldman and Heilig laboratories indicate that loss of this receptor contributes to increased ethanol drinking and preference in both rat and mouse. It will be interesting to determine the contribution to these phenotypes of mGluR2 at corticostriatal synapses.

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。纹状体突触可塑性和滥用药物的影响我们已经检查了DS内突触时的许多形式的突触可塑性。最突出的之一是通过激活GI/O类G蛋白偶联受体（GPCR）激活的谷氨酸能皮质层状突触的长期抑郁（LTD）。除了由大麻素1型（CB1）和5-羟色胺1B受体激活引起的LTD外，我们还观察到阿片类肽的MU，Delta和Kappa受体的激活可能诱导LTD。同样，抑制阿片类肽分解代谢诱导LTD，这种突触抑制似乎涉及三种受体亚型内源性阿片类肽的作用。由MU和Delta阿片受体诱导的LTD的表达涉及谷氨酸释放的概率降低，类似于CB1依赖性LTD的机理。实际上，MU阿片受体和CB1依赖性有限公司可以在另一个依赖性的LTD上阻塞，表明它们在突触的重叠群体中共享机制。相反，MU依赖性有限公司不能阻止三角洲阿片受体依赖性LTD，这表明这两种阿片类药物介导的突触可塑性形式的单独作用部位。我们已经检查了对体内暴露于广泛规定和严重滥用的阿片类药物受体激动剂氧酮和乙醇的影响。单一注射羟考酮在体内导致MU-和CB1依赖性LTD的损失。一次药物注射后，该效果持续长达4天。体内羟考酮注射对三角体受体介导的有限公司没有影响。在体内2-4周暴露于陶醉的乙醇浓度后，观察到Mu-和Cb1依赖性LTD的类似损失。因此，某些形式的突触前有限公司的损害似乎是不同滥用药物产生的常见损害。 Ltd的损失可能会改变纹状体培养基神经元的皮质控制，这可能导致乙醇等药物产生的纹状体依赖性学习的改变，也许会导致寻求习惯性药物。重要的是要弄清楚体内药物暴露会如何损害涉及LTD的机制。代谢型谷氨酸受体2（MGLUR2）是另一种突触前受体，与皮质纹状体谷氨酸盐辅助酶的调节和长期抑郁有关。与Drs的实验室合作。 David Goldman和Markus Heilig在NIAAA，我们已经证实，在该基因（GRM2基因）中产生过早的终止密码子的多态性导致该受体在酒精优先（P）大鼠中的功能丧失。在皮质纹状体突触中，突触前受体功能完全丧失。高盛和海里格实验室进行的研究表明，这种受体的丧失有助于增加大鼠和小鼠的乙醇饮用和偏爱。确定对皮质纹状体突触中MGLUR2表型的贡献将很有趣。