The Role of Amygdalar Endocannabinoids in Alcohol Drinking after Traumatic Brain Injury (TBI)

杏仁核内源性大麻素在脑外伤 (TBI) 后饮酒中的作用

• 批准号: 10196893
• 负责人: Zachary Stielper
• 金额: $ 3.6万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-05-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196893
• 关键词: 2-arachidonylglycerol; 2-arachidonylglycerol signaling; Acute; Addictive Behavior; Adult; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; American; Amygdaloid structure; Animal Model; Animals; Anxiety; Behavioral; Brain; Brain region; CNR1 gene; Chronic; Chronic Brain Injury; Clinic; Craniotomy; Data; Development; Doctor of Medicine; Dose; Endocannabinoids; Enzymes; Exhibits; FOS gene; Fellowship; Female; Foundations; Functional disorder; Glutamates; Health; Homeostasis; Hour; Human; Immunohistochemistry; Impaired cognition; Injections; Injury; Lateral; Liquid substance; MAGL inhibitor; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Mental Depression; Modeling; Molecular; Monoacylglycerol Lipases; NAPE-PLD; Neurobiology; Neurologic; Neurons; Neurosciences Research; Outcome; Patients; Percussion; Pharmacology; Physicians; Public Health; Pyramidal Cells; Rattus; Regulation; Reporting; Research Project Grants; Research Training; Risk Factors; Rodent; Role; Scientist; Self Administration; Signal Transduction; Signaling Protein; Stress; Synapses; Synaptic Transmission; Testing; Therapeutic Intervention; Time; Training; Traumatic Brain Injury; Western Blotting; Wistar Rats; Work; alcohol effect; alcohol exposure; alcohol research; alcohol use disorder; anandamide; anxiety states; anxiety-like behavior; biological adaptation to stress; cannabinoid receptor; career; comorbidity; cost; doctoral student; effective therapy; efficacy evaluation; endocannabinoid signaling; endogenous cannabinoid system; experimental study; glutamatergic signaling; hippocampal pyramidal neuron; inhibitor/antagonist; injury-related death; male; mild traumatic brain injury; neurobehavioral; receptor; retrograde transport; synthetic enzyme; therapeutically effective; transmission process; treatment strategy; withdrawal-induced anxiety

PROJECT ABSTRACT Traumatic brain injury (TBI) and alcohol-use disorder (AUD) each pose significant burdens to public health: approximately 2.5 million Americans incur a TBI annually, and roughly 7.2% of American adults (~17 million) have an AUD. Of particular importance is the reciprocal interaction of these two health issues: alcohol intoxication is a major risk factor for incurring a TBI, TBI drives escalation of alcohol drinking in human patients and animal models, and TBI neurobehavioral sequelae are worsened by alcohol intoxication at time of TBI and by post-TBI alcohol drinking. Approximately 25% of TBI patients report heavy or problematic alcohol drinking one year post- TBI, regardless of pre-injury alcohol intake. Unfortunately, neither the neurological mechanisms by which alcohol exacerbates TBI pathophysiology nor the mechanisms by which TBI stimulates escalation of alcohol consumption are well-understood. The basolateral amygdala (BLA) mediates stress responses and anxiety-like behavior, and is impacted by acute and chronic alcohol. BLA glutamatergic pyramidal neurons contribute to escalated alcohol drinking and alcohol withdrawal-induced anxiety-like behavior. Regulation of synaptic input onto BLA pyramidal neurons is mediated, at least in part, by endocannabinoids (eCBs). In the brain, eCBs (2- arachidonylglycerol [2-AG] and anandamide [AEA]) transport retrogradely to activate pre-synaptic cannabinoid receptors, thereby inhibiting glutamatergic and GABAergic transmission. eCB signaling mediates alcohol effects on BLA synaptic transmission: for example, acute alcohol produces eCB-dependent decreases in excitatory transmission and increases in inhibitory transmission in BLA, and these effect may be mediated by 2-AG. Type- 1 cannabinoid receptors (CB1Rs) on BLA glutamatergic terminals mediate eCB effects on anxiety-like behavior, and chronic intermittent alcohol exposure augments excitatory BLA transmission by selectively down-regulating CB1R on glutamatergic terminals in BLA. Therefore, 2-AG signaling at CB1R modulates BLA glutamatergic transmission, and may be a promising target for reducing post-TBI escalation of alcohol drinking. Here, we propose to use a rodent lateral fluid percussion (LFP) model of mild TBI to examine the neurobiological basis for co-morbid TBI and AUD. Specifically, we will test the role of BLA endocannabinoids in post-TBI escalation of alcohol drinking. Female and male Wistar rats will be trained to self-administer alcohol in an operant setting, and will undergo craniotomy before half of all rats receive TBI via LFP. In all experiments, we will use male and female alcohol-drinking Wistar rats that undergo mild TBI or sham injury: we will use c-fos immunohistochemistry to measure BLA neuronal activation, Western blots to measure eCB system components (i.e., receptors, synthetic enzymes, and degradative enzymes) in BLA, and mass spectroscopy to measure eCB levels in BLA. We will also measure the activity of the major 2-AG degradative enzyme, monoacylglycerol lipase. Finally, we will test the prediction that intra-BLA injection of MAGL inhibitor, JZL184, blocks post-TBI escalation of alcohol self-administration. Our overall hypotheses are that TBI reduces eCB signaling and CB1R expression in BLA, and that increasing 2-AG levels in BLA will rescue post-TBI escalation of alcohol drinking. The proposed experiments will (1) investigate the effects of TBI on BLA eCB system of alcohol-drinking rats and (2) evaluate the efficacy of pharmacologic eCB modulation in blocking post-TBI escalation of alcohol self-administration. Additionally, the experiments and activities described in this proposal will provide a promising M.D./Ph.D. student with research training and professional development that will form the foundation for a successful career as a physician-scientist conducting translational alcohol research.

项目摘要