Control Of Behavior By Drug Injections

通过药物注射控制行为

• 批准号: 8148485
• 负责人: Steven Goldberg
• 金额: $ 119.64万
• 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/8148485
• 关键词: Behavior Control; Dopamine; Endocannabinoids; Injection of therapeutic agent; Pharmaceutical Preparations; prevent

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 neurobiological 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 alpha4_beta2* 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 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 electrophysiology experiments showed that URB597 blocked the activation of dopamine neurons in the ventral tegmental area by nicotine and in vivo microdialysis experiments showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the two main areas of the brain's 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.

在人类中具有滥用倾向的药物通常充当正向抑制剂以维持和加强导致其在动物中施用的行为，并充当控制双杠杆选择行为的辨别刺激。正在进行实验，以评估大鼠和猴子的药物自我给药行为和药物控制行为的神经生物学和行为机制，以及药理学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还没有得到很好的理解。烟碱乙酰胆碱受体（nAChR）的中脑α 4_β 2 * 亚型已经涉及负责依赖性的尼古丁的增强作用的介导。然而，尚未进行研究评估中脑nAChR水平的个体间差异对自我给予尼古丁的动机的影响。我们使用2-18Ffluoro-A-85380和正电子发射断层扫描（PET）在松鼠猴中测量了α 4 β 2 nAChR的基线水平。随后使用渐进比例强化计划测量自我给予尼古丁的动机（杠杆按压次数）。自我给予尼古丁的更大动机与中脑α 4-β 2 nAChR水平较低相关。因此，α 4-β 2 nAChR的基线表达可预测自我给予尼古丁的动机。 新出现的证据表明，尼古丁的奖励，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，大麻素CB 1受体的药理学阻断或遗传缺失减少或消除了尼古丁的许多滥用相关的行为和神经化学作用。此外，单独使用时无效的天然大麻素δ-9-四氢大麻酚和尼古丁的剂量在一起使用时会诱导条件性位置偏好。这些先前的研究使用了全身给予的CB 1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的大麻素CB 1受体。改变内源性大麻素活性的一种更具功能选择性的方法是抑制脂肪酸酰胺水解酶（FAAH），从而仅在内源性大麻素anandamide按需合成和释放时放大和延长其作用。在这里，我们结合行为和神经化学方法来评估FAAH抑制剂URB 597是否可以改变大鼠中尼古丁的滥用相关效应。我们发现，URB 597，在一个剂量，本身没有行为的影响，防止尼古丁诱导的条件性位置偏爱（CPP）的发展和收购尼古丁自我管理。URB 597还减少了尼古丁诱导的CPP和自我给药复发模型的复发。此外，在体内电生理学实验表明，URB 597阻断腹侧被盖区的多巴胺神经元的激活尼古丁和在体内微透析实验表明，URB 597减少尼古丁诱导的多巴胺升高的核壳，两个主要领域的大脑的mesolimbic奖励系统。这些研究结果表明，FAAH抑制可以抵消尼古丁的成瘾特性，FAAH可以作为开发治疗烟草依赖药物的新靶点。 尼古丁刺激中脑边缘多巴胺神经元的活动，这被认为是介导烟草使用的奖励和成瘾特性。我们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尼古丁效应的调制与电生理技术在体内和体外。我们发现，FAAH的药理学抑制，脂肪酸乙醇酰胺分解代谢的酶，其中内源性大麻素anandamide是最有名的，抑制尼古丁诱导的多巴胺细胞的兴奋。重要的是，这种作用通过施用FAAH底物油酰乙醇胺（OEA）和棕榈酰乙醇胺（PEA）而不是AEA的抗水解类似物甲满草胺来模拟。OEA和PEA是天然存在的脂质信号传导分子，结构上与大麻素相关，但对大麻素受体缺乏亲和力。他们通过激活过氧化物酶体增殖物激活受体α（PPAR α）来阻断尼古丁的作用，过氧化物酶体增殖物激活受体α是一种参与脂质代谢和能量平衡多个方面的核受体转录因子。激活的过氧化物酶体增殖物激活受体-α触发了酪氨酸激酶的非基因组刺激，这可能导致磷酸化和神经元烟碱乙酰胆碱受体的负调节。这些数据首次表明，尼古丁脂质OEA和PEA具有作为大脑中PPAR-alpha的内源性配体的神经调节特性，并为尼古丁成瘾的治疗提供了潜在的新靶点。