Drugs On Learned & Spontaneous Behavior Of Experimental Animals

药物学习

• 批准号: 8148486
• 负责人: Steven Goldberg
• 金额: $ 97.89万
• 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/8148486
• 关键词: Animals; Behavior; Learning; Pharmaceutical Preparations

Experiments are being conducted to assess the different neuropharmacological and behavioral mechanisms underlying behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify discrimination, as well as self-administration, of THC or nicotine, to disrupt ongoing food-maintained behavior to alter emotional responses such as anxiety or to modulate attention learning and memory processes. Currently, studies are focusing on nicotine and a series of cannabinoids, including delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, the cannabinoid CB1 receptor antagonists Rimonabant and AM251, and AM4113, the endogenous cannabinoids anandamide and 2AG, the non-cannabinoid fatty acid amides OEA and PEA, the anandamide uptake inhibitor AM404, and the fatty acid amide hydrolase (FAAH) inhibitor URB597. Studies are also being conducted on methamphetamine, cocaine and heroin. Endocannabinoids are involved in a variety of behavioral and physiological processes that are just beginning to be understood. Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB1-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for a-type peroxisome proliferatoractivated nuclear receptors, PPAR- alpha) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-alpha agonist WY14643, and these enhancements were blocked by the PPAR- alpha antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR- alpha, either directly by administering a PPAR- alpha agonist or indirectly by administering a FAAH inhibitor. In the five-choice serial reaction time task, exogenous cannabinoids have been found to alter attention, but endocannabinoids such as anandamide have not been studied. We used this task to evaluate the effects of anandamide in rats. Since anandamide is a ligand for not only cannabinoid receptors but also transient receptor potential vanilloid 1 (TRPV1) receptors, and as recently suggested, peroxisome proliferator-activated nuclear receptor- (PPAR), we also determined whether anandamides effects in this task were mediated by each of these receptors. Anandamide increased omission errors and decreased responding during inter-trial intervals. These effects were blocked by the TRPV1 antagonist capsazepine, but not by the cannabinoid-receptor antagonist rimonabant or the PPAR- alpha antagonist MK886. Testing with open-field activity and food-consumption procedures in the same rats suggested that the disruption of operant responding observed in the attention task was not due to motor depression, anxiety, decreased appetite, or an inability to find and consume food pellets. Thus, the vanilloid-dependent behavioral disruption induced by anandamide was specific to the operant attention task. These effects of anandamide resemble effects of systemically administered dopamine antagonists and might reflect changes in vanilloid-mediated dopamine transmission. The enzyme FAAH is a promising target for anxiety-related disorders. FAAH inhibitors (e.g., URB597) increase brain levels of anandamide and induce anxiolytic-like effects in rodents. Recent findings, however, questioned the efficacy of FAAH inhibitors as anxiolytics due to inconsistent findings in different labs. We tested here the hypothesis that conflicting findings are due to variations in the stressfulness of experimental conditions employed in various studies. We found that URB597 did not produce anxiolytic effects when the aversiveness of testing procedures was minimized by handling rats daily before experimentation, by habituating them to the experimental room, or by employing low illumination during testing. In contrast, URB597 had robust anxiolytic effects when the aversiveness of the testing environment was increased by eliminating habituation to the experimental room or by employing bright lighting conditions. Unlike URB597, the benzodiazepine chlordiazepoxide (5 mg/kg) had anxiolytic effects under all testing conditions. The anxiolytic effects of URB597 were abolished by the cannabinoid CB1-receptor antagonist AM251, showing that they were mediated by CB1 receptors. Our findings show that FAAH inhibition does not affect anxiety under mildly stressful circumstances but protects against the anxiogenic effects of aversive stimuli.

正在进行实验，以评估不同的神经药理学和行为机制的基础上的行为控制的药物作为区分刺激在大鼠和猴子和药理学或行为操纵的能力，以修改歧视，以及自我管理，THC或尼古丁，破坏正在进行的食物维持行为，改变情绪反应，如焦虑或调节注意力学习和记忆过程。目前，研究集中在尼古丁和一系列大麻素，包括大麻中的精神活性成分δ-9-四氢大麻酚（THC）、大麻素CB 1受体拮抗剂利莫那班和AM 251、AM4113、内源性大麻素anandamide和2AG、非大麻素脂肪酸酰胺OEA和PEA、anandamide摄取抑制剂AM404、和脂肪酸酰胺水解酶（FAAH）抑制剂URB 597。还正在对甲基安非他明、可卡因和海洛因进行研究。 内源性大麻素参与各种行为和生理过程，这些过程刚刚开始被理解。脂肪酸酰胺水解酶（FAAH）的抑制剂增加大麻素（大麻素CB 1-受体配体）和油酰乙醇酰胺和棕榈酰乙醇酰胺（OEA和PEA，α-型过氧化物酶体增殖物激活的核受体（PPAR-alpha）的配体）在脑中自然释放时的内源性水平。在大鼠中使用被动回避任务，我们发现FAAH抑制剂URB 597或PPAR-alpha激动剂WY 14643增强了记忆获得，并且这些增强被PPAR-alpha拮抗剂MK 886阻断。这些发现证明了通过直接给予PPAR-α激动剂或间接给予FAAH抑制剂激活PPAR-α来增强记忆的新机制。 在五选择系列反应时间任务中，外源性大麻素被发现可以改变注意力，但内源性大麻素如大麻素还没有被研究过。我们用这个任务来评估大麻素在大鼠中的作用。由于大麻素不仅是大麻素受体的配体，也是瞬时受体电位香草素1（TRPV 1）受体的配体，正如最近提出的，过氧化物酶体增殖物激活核受体（PPAR），我们还确定了大麻素在这项任务中的作用是否由这些受体中的每一个介导。在试验间隔期间，Anandamide增加遗漏错误并减少反应。这些作用被TRPV 1拮抗剂辣椒平阻断，但不能被大麻素受体拮抗剂利莫那班或PPAR-alpha拮抗剂MK 886阻断。在相同大鼠中进行的旷场活动和食物消耗程序测试表明，在注意力任务中观察到的操作性反应中断不是由于运动性抑郁、焦虑、食欲下降或无法找到和消耗食物颗粒。因此，由花生四烯酸引起的香草素依赖性行为中断是特定于操作性注意任务的。花生四烯酸酰胺的这些作用类似于全身给药的多巴胺拮抗剂的作用，可能反映了香草素介导的多巴胺传递的变化。 酶FAAH是一个有前途的目标焦虑相关的疾病。FAAH抑制剂（例如，URB 597）增加脑中大麻素的水平，并在啮齿动物中诱导抗焦虑样作用。然而，最近的研究结果质疑FAAH抑制剂作为抗焦虑药的疗效，因为不同实验室的结果不一致。我们在这里测试的假设，相互矛盾的结果是由于在不同的研究中采用的实验条件的压力变化。我们发现，URB 597没有产生抗焦虑作用时，通过每天处理大鼠实验前，通过使它们习惯于实验室，或通过采用低照明在测试过程中，测试程序的厌恶性最小化。相反，当通过消除对实验室的习惯或通过采用明亮的照明条件来增加测试环境的厌恶度时，URB 597具有强大的抗焦虑作用。与URB 597不同，苯二氮卓类和氯氮卓类（5 mg/kg）在所有试验条件下均具有抗焦虑作用。URB 597的抗焦虑作用被大麻素CB 1受体拮抗剂AM 251消除，表明它们是由CB 1受体介导的。我们的研究结果表明，FAAH抑制并不影响焦虑在轻度压力的情况下，但防止焦虑的厌恶性刺激的影响。