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Endocannabinoid and other brain receptor systems roles in neurochemical and reinforcing effects of abused drugs

内源性大麻素和其他大脑受体系统在神经化学和增强滥用药物作用中的作用

基本信息

批准号：
10267545
负责人：
Gianluigi Tanda
金额：
$ 56.76万
依托单位：
NATIONAL INSTITUTE ON DRUG ABUSE
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/10267545
关键词：
2-arachidonylglycerol AM404 Acute Affect Agonist Agreement Animal Model Animals Astrocytes Attenuated Behavior Behavioral Brain CB1 receptor antagonist CNR1 gene Cannabinoids Cannabis Chemosensitization Cholinergic Antagonists Corpus striatum structure Data Development Disease Dopamine Dose Electroencephalography Electrophysiology (science)Endocannabinoids Enhancers Enzyme Inhibitor Drugs Enzymes Ethanol Food Frequencies Functional disorder Glutamates Heroin Hour Human In Situ Hybridization In Vitro Injections Intravenous Ketamine Kynurenic Acid Kynurenine Kynurenine 3-monooxygenase Learning Ligands Lipase Lipopolysaccharides Measures Medial Mediating Mental disorders Messenger RNA Metabolism Microdialysis Modeling Molecular Conformation Monkeys Morphine Motor Activity NMDA receptor antagonist Naloxone Naltrexone Negative Finding Nerve Neurobiology Neurodegenerative Disorders Neuropeptides Neurotransmitters Nicotine Nucleus Accumbens Opiate Addiction Opioid Opioid agonist Oxytocin Oxytocin Receptor Pathway interactions Pharmaceutical Preparations Pharmacological Treatment Pharmacology Play Pre-Clinical Model Prefrontal Cortex Procedures Psychiatric therapeutic procedure Psychological reinforcement Rattus Relapse Reporting Rewards Rhodobacter sphaeroides Ritalin Rodent Role Route Saline Self Administration Slice Specificity Stress Substance Use Disorder System TLR4 gene Testing Therapeutic Effect Time Training Ventral Tegmental Area Withdrawal alpha-bungarotoxin receptor anandamide craving drug action drug development drug of abuse endogenous cannabinoid system extracellular fatty acid amide hydrolase gamma-Aminobutyric Acid hippocampal pyramidal neuron in vivo inhibitor/antagonist interest intraperitoneal memory process methyllycaconitine mu opioid receptors neurobiological mechanism neurochemistry neurotransmission opioid abuse opioid use disorder opioid withdrawal pre-clinical preclinical study preference prevent psychostimulant receptor reinforcer remifentanil response rimonabant side effect social

项目摘要

We have discovered that endogenous cannabinoids possess reinforcing effects assessed by self-administration procedures. Also, systemic administration of endogenous cannabinoid agonists would increase extracellular levels of DA. The endogenous cannabinoid agonist 2AG produces a small, transient increase in DA levels in the nucleus accumbens shell (NAS). This is in agreement with reports showing that 2AG is usually very rapidly metabolized in vivo by a specific enzyme, mono-acyl-glyceryl-lipase (MAGL). We have now available a drug, AM-4301, that would selectively block the activity of the MAGL enzyme. By blocking this enzyme we should be able to potentiate the behavioral and neurochemical effects of 2AG. When tested alone, AM-4301 slightly decreased levels of NAS DA in rats. When administered in combination with 2AG the results show a larger increase in DA than with 2AG alone. It is interesting to note that our preliminary tests show that AM-4301 might be interacting with the MAGL enzyme with a delayed onset and longer-lasting action. Indeed we found a larger increase in DA after AM-4301 pretreatments in animals injected with 2-AG, when the pretreatment time was 24 hours as compared to 40 or 60 minutes. Reward-related behavioral and neurochemical effects of THC, the main psychoactive ingredient in cannabis, could be blocked by methyl-lycaconitine (MLA), a selective antagonist of alpha7-nAChRs, expressed by glutamatergic nerve terminals in both the VTA and the NAS. Their activation elicits GLU release activating ionotropic GLUR on DAergic terminals to stimulate DA release. Systemic use of direct antagonists of alpha7-nAChRs is associated with unwanted side effects that might be avoided by using endogenous negative allosteric modulators of alpha7nAChRs, like kynurenic acid (KYNA). KYNA should be better tolerated than directly acting cholinergic antagonists. Allosteric modulators change receptors conformation in the presence of orthosteric ligands and often have no effect on their own. We tested Ro 61-8048, an inhibitor of the kynurenine 3-monooxygenase (KMO) enzyme that indirectly increase the endogenous levels of KYNA. KYNA is synthesized by astroglia and is promptly released into the extracellular compartment. Astroglia also express functional alpha7nAChRs and CB1Rs. We have shown that the reinforcing and related dopamine-releasing effects of THC can be attenuated by increasing endogenous levels of KYNA through systemic administration of Ro 61-8048. We then tested whether an allosteric modulation of alpha7nAChRs, and activation of CB1Rs could regulate glutamate release. We used rat in vivo microdialysis, electrophysiology, RNAscope in situ hybridization in brain slices, and primary culture of rat cortical astrocytes. Acute systemic administration of THC increased extracellular levels of glutamate in the NAS, ventral tegmental area (VTA) and medial prefrontal cortex (mPFC). THC also reduced extracellular levels of KYNA in the NAS. These THC effects were prevented by administration of Ro 61-8048 or the CB1R antagonist, rimonabant. THC increased the firing activity of glutamatergic pyramidal neurons projecting from the mPFC to the NAS or to the VTA in vivo. These effects were prevented by pretreatment with Ro 61-8048. In vitro, THC elicited glutamate release from cortical astrocytes (on which we demonstrated co-localization of the CB1Rs and alpha7nAChRs mRNAs), and this effect was prevented by KYNA and rimonabant. These results suggest a key role of astrocytes in interactions between the endocannabinoid system, kynurenine pathway and glutamatergic neurotransmission, with ramifications for the pathophysiology and treatment of psychiatric and neurodegenerative diseases. In a recent study, using EEG procedures in rats treated acutely with drugs abused by humans, we have characterized the changes in alpha, beta, gamma delta and theta bands. The mu-opioid receptor agonists heroin and morphine dose-dependently decreased the power of gamma and increased power of the other bands. The effect of morphine on EEG power bands was antagonized by naltrexone. The NMDA receptor antagonist ketamine increased the power of all frequency bands. Our data show how drugs of abuse belonging to different classes may differentially affect EEG spectra, showing distinctive features in the magnitude and direction of their effects on EEG. These data suggest that EEG can be used to rapidly screen compounds for potential activity at specific pharmacological targets and provide valuable information for guiding the early stages of drug development. Recently, we have investigated the effect of OT, delivered intraperitoneally (i.p.), on the methylphenidate (MP) dose response function for behavioral and neurochemical actions in rats. Food was used as a control condition. In a microdialysis study we measured the effect of OT on MP-stimulated striatal DA levels. Systemic OT pretreatment caused a downward shift in the MP dose response function while having no effect on motor activity. OT also caused a reduction in food self-administration, although a significantly higher dose of OT was required for this effect compared to that required for a reduction of MP self-administration. Systemic OT pretreatment caused a potentiation of MP-stimulated DA levels in the NAS but not in the core. Our findings suggest that OT might be tested in humans as a potential pharmacologic treatment for psychostimulant use disorders. We are now studying the effects of OT administered intranasally, as this route of administration has been suggested to be the preferred one for OT in preclinical studies. The Toll-like receptor 4 (TLR4) antagonists, (+)-naloxone and (+)-naltrexone, have been reported to decrease self-administration of opioids in rats and to reduce other preclinical indicators of abuse potential. The objectives of the current study were to further characterize the reinforcer specificity of TLR4 antagonism in opioid self-administration and to explore its effects in a preclinical model of craving/relapse. The TLR4 antagonist (+)-naltrexone decreased responding in rats trained to self-administer the -opioid receptor agonist remifentanil, but with a potency that was not significantly different from that observed in another group of subjects in which responding was maintained by food reinforcement. Responding reinstated by heroin injection was decreased by (+)-naltrexone; however, a similar reduction was not reproduced with the administration of another TLR4 antagonist, lipopolysaccharide from Rhodobacter sphaeroides, administered into the NAS. Thus, TLR4 antagonists lacked reinforcer selectivity in reducing opioid self-administration and were not uniformly effective in a model of craving/relapse, suggesting limitations on the development of (+)-naltrexone or TLR4 antagonists as treatments for opioid abuse.

我们已经发现，内源性大麻素具有强化效应评估的自我管理程序。此外，内源性大麻素激动剂的全身管理将增加细胞外水平的DA。内源性大麻素激动剂2AG在伏隔核壳（NAS）中产生小的，短暂的DA水平增加。这与有报道表明2AG通常在体内被一种特殊的酶——单酰基甘油脂肪酶（MAGL）快速代谢的结果一致。我们现在有一种药物，AM-4301，可以选择性地阻断MAGL酶的活性。通过阻断这种酶，我们应该能够增强2AG的行为和神经化学作用。单独测试时，AM-4301略微降低大鼠NAS DA水平。当与2AG联合使用时，结果显示DA比单独使用2AG增加更大。有趣的是，我们的初步测试表明，AM-4301可能与MAGL酶相互作用，并具有延迟起效和更持久的作用。事实上，我们发现注射2-AG的动物在AM-4301预处理后DA增加更大，预处理时间为24小时，而不是40或60分钟。