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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

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.

综合神经科学实验室内的研究，突触药理学部分，继续侧重于神经调节和可塑性的机制，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侧纹状体（DS）的功能，这是一个涉及动作控制和选择以及动作学习的大脑区域。纹状体突触可塑性与药物滥用的影响我们已经研究了DS内突触的多种形式的突触可塑性。其中最突出的是通过G蛋白偶联受体（GPCR）的Gi/o类的激活产生的多巴胺能皮质纹状体突触的长期抑制（LTD）。除了大麻素1型（CB 1）和血清素1B型受体的激活诱导的LTD，我们还观察到，阿片肽的μ，δ和κ受体的激活可以诱导LTD。同样，阿片肽catalysts的抑制诱导LTD，这种突触抑制似乎涉及内源性阿片肽在三种受体亚型的作用。由μ和δ阿片受体诱导的LTD的表达涉及谷氨酸释放的可能性降低，类似于CB 1依赖性LTD的机制。事实上，μ阿片受体和CB 1依赖性LTD可以彼此闭塞，表明它们在重叠的突触群体中共享机制。相反，δ阿片受体依赖性LTD不能被μ依赖性LTD阻断，表明这两种阿片介导的突触可塑性形式的作用部位不同。我们研究了在体内暴露于广泛使用和严重滥用的阿片受体激动剂羟考酮以及乙醇对纹状体LTD的影响。体内单次注射羟考酮可导致mu和CB 1依赖性LTD丧失。单次药物注射后，该效应持续长达4天。体内羟考酮注射液对δ受体介导的LTD没有影响。在体内暴露于致醉浓度的乙醇2-4周后，观察到mu和CB 1依赖型LTD的类似损失。因此，某些形式的突触前LTD的损害似乎是不同药物滥用产生的常见损害。 LTD的丧失可能会改变纹状体中等多刺神经元的皮质控制，可能有助于改变药物（如乙醇）产生的纹状体依赖性学习，也可能有助于习惯性药物寻求。重要的是要弄清楚LTD中涉及的机制如何被体内药物暴露所损害。代谢型谷氨酸受体2（mGluR 2）是另一种突触前受体，与皮质纹状体谷氨酸能综合征的调节和长期抑制有关。通过与NIAAA的大卫戈德曼和马库斯·海利格博士的实验室合作，我们已经证实，在该基因（grm 2基因）中产生提前终止密码子的多态性导致了酒精偏好（P）大鼠中该受体功能的丧失。突触前受体功能在皮质纹状体突触处完全丧失。 Goldman和Heilig实验室进行的研究表明，这种受体的缺失有助于增加大鼠和小鼠的乙醇饮用和偏好。这将是有趣的，以确定这些表型的mGluR 2在皮质纹状体突触的贡献。