Control Of Behavior By Drug Injection

通过药物注射控制行为

• 批准号: 7966738
• 负责人: Steven Goldberg
• 金额: $ 127.33万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 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/7966738
• 关键词: Affect; Affinity; Agonist; Animals; Area; Behavior; Behavior Control; Behavioral; Behavioral Mechanisms; Brain; CNR1 gene; Cannabinoids; Cells; Choice Behavior; Cocaine; Data; Dependence; Development; Dopamine; Dose; Drug Addiction; Endocannabinoids; Enzymes; Fatty Acids; Freedom; Gene Deletion; Genetic; Goals; Human; Hydrolysis; In Vitro; Individual; Individual Differences; Injection of therapeutic agent; Lead; Ligands; Lipids; Marijuana; Measures; Mediating; Mediation; Methamphetamine; Microdialysis; Midbrain structure; Modeling; Monkeys; Motivation; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nuclear Receptors; Nucleus Accumbens; PPAR alpha; Pharmaceutical Preparations; Pharmacological Treatment; Phosphorylation; Positive Reinforcer; Positron-Emission Tomography; Property; Protein Tyrosine Kinase; Rattus; Regulation; Reinforcement Schedule; Relapse; Research; Resistance; Rewards; Saimiri; Self Administration; Self-Administered; Signaling Molecule; Stimulus; System; Techniques; Tetrahydrocannabinol; Time; Tobacco; Tobacco Dependence; Tobacco use; Ventral Tegmental Area; analog; anandamide; cannabinoid receptor; dopaminergic neuron; drug of abuse; drug seeking behavior; energy balance; fatty acid amide hydrolase; in vivo; inhibitor/antagonist; interest; lipid metabolism; methanandamide; mortality; neurochemistry; non-genomic; oleoylethanolamide; palmidrol; preference; prevent; research study; transcription factor

Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and serve as discriminative stimuli controlling two-lever choice behavior. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug self-administration behavior and behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Tobacco dependence is the leading preventable cause of mortality in the world and nicotine appears to be the main critical psychoactive component in establishing and maintaining tobacco dependence. Marked inter-individual differences in vulnerability to nicotine dependence exist, but factors underlying such differences are not well understood. The midbrain _4_2* subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediation of the reinforcing effects of nicotine responsible for dependence. However, no study has been performed evaluating the impact of inter-individual differences in midbrain nAChR levels on motivation to self-administer nicotine. We measured baseline levels of alpha 4 beta 2 nAChRs using 2-18Ffluoro-A-85380 and positron emission tomography (PET) in squirrel monkeys. Motivation to self-administer nicotine (number of lever presses) was subsequently measured using a progressive-ratio schedule of reinforcement. Greater motivation to self-administer nicotine was associated with lower levels of midbrain alpha4-beta2 nAChRs. Thus, baseline expression of alpha4-beta2 nAChRs predicts motivation to self-administer nicotine. Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB1 receptors reduces or eliminates many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of the natural cannabinoid delta-9-tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preferences when given together. These previous studies have used systemically administered CB1 receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB1 receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of the endocannabinoid anandamide only when and where it is synthesized and released on demand. Here, we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor URB597 could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brains mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence. Nicotine stimulates the activity of mesolimbic dopamine neurons, and this is believed to mediate the rewarding and addictive properties of tobacco use. We have investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area of rats with electrophysiological techniques both in vivo and in vitro. We discovered that pharmacological inhibition of FAAH, the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to anandamide, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor- alpha (PPAR alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR- alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.

在人类身上有滥用倾向的药物通常作为积极的增强剂，维持和加强导致它们在动物身上使用的行为，并作为歧视性刺激，控制两级选择行为。正在进行实验，以评估潜在的神经药理学和行为机制，药物自我给药行为和由药物控制的行为在大鼠和猴子中作为区别刺激，以及药物或行为操纵改变这种行为的能力。 烟草依赖是世界上主要的可预防的死亡原因，尼古丁似乎是建立和维持烟草依赖的主要关键精神活性成分。尼古丁依赖的易感性存在明显的个体间差异，但这种差异背后的因素尚未得到很好的理解。烟碱型乙酰胆碱受体(NAChRs)的中脑_4_2*亚型参与了尼古丁对依赖的强化作用。然而，还没有研究评估中脑nAChR水平的个体差异对自我服用尼古丁动机的影响。我们用2-18FFluo-A-85380和正电子发射断层扫描测量了松鼠猴的α-4-β-2nAChRs的基线水平。随后，使用累进比率强化计划来测量自我给予尼古丁的动机(杠杆按压次数)。自我服用尼古丁的更大动机与较低的中脑α4-β2 nAChRs水平相关。因此，α4-β2 nAChRs的基线表达预测了自我给药尼古丁的动机。 新出现的证据表明，尼古丁的回报和滥用相关的影响是由大脑的内源性大麻素系统调节的。例如，药物阻断或大麻素CB1受体的基因缺失减少或消除了尼古丁的许多与滥用有关的行为和神经化学影响。此外，单独给药时无效的天然大麻素-9-四氢大麻酚和尼古丁剂量在一起给药时可以诱导条件性地点偏爱。这些先前的研究使用了系统地给药CB1受体激动剂和拮抗剂以及基因缺失技术，这些技术影响整个大脑中的大麻素CB1受体。一种更具功能选择性的改变内源性大麻素活性的方法是抑制脂肪酸酰胺水解酶(FAAH)，从而仅在合成和根据需要释放内源性大麻酰胺时放大和延长内源性大麻酰胺的作用。在这里，我们结合行为和神经化学方法来评估FAAH抑制剂URB597是否可以改变大鼠尼古丁滥用相关的影响。我们发现，URB597剂量(0.3 mg/kg)本身没有行为影响，可以阻止尼古丁诱导的条件性位置偏爱(CPP)的形成和尼古丁自我给药的获得。URB597还减少了CPP和自我给药复发模型中尼古丁诱导的恢复。此外，体内微透析显示，URB597减少了尼古丁诱导的伏隔核壳内多巴胺的升高，伏隔核壳是大脑中脑边缘奖赏系统的末端区域。这些发现表明，FAAH抑制可以抵消尼古丁的成瘾特性，FAAH可能成为治疗烟草依赖药物开发的新靶点。 尼古丁刺激中脑边缘多巴胺神经元的活动，这被认为是烟草使用的奖赏和成瘾特性的中介。我们在体内和体外用电生理技术研究了内源性大麻素系统对大鼠腹侧被盖区多巴胺神经元的调节作用。我们发现，FAAH是一种分解脂肪酸乙醇酰胺的酶，其中最著名的是内源性大麻酰胺，它的药理抑制抑制了尼古丁诱导的多巴胺细胞的兴奋。重要的是，FAAH底物油酰乙醇胺(OEA)和棕榈酰乙醇胺(PEA)的给药模拟了这种作用，但不能给AEA的耐水解类似物甲烷胺。OEA和PEA是天然存在的脂质信号分子，在结构上与Anandamide有关，但与大麻素受体缺乏亲和力。他们通过激活过氧化体增殖物激活受体α(PPARα)来阻断尼古丁的影响，PPARα是一种核受体转录因子，参与脂质代谢和能量平衡的多个方面。PPAR-α的激活触发了酪氨酸激酶的非基因组刺激，这可能导致神经元烟碱型乙酰胆碱受体的磷酸化和负调节。这些数据首次表明，厌食性脂质OEA和PEA作为脑内PPAR-α的内源性配体具有神经调节作用，为尼古丁成瘾的治疗提供了一个潜在的新靶点。