Drugs On Learned & Spontaneous Behavior Of Experimental Animals

正在进行实验，以评估不同的神经药理学和行为机制潜在的药物控制的行为作为区别刺激的大鼠和猴子，以及药物或行为操纵的能力，以改变对THC或尼古丁的歧视，以及自我给药，扰乱正在进行的食物维持的行为，改变焦虑等情绪反应，或调节注意力学习和记忆过程。目前，研究的重点是尼古丁和一系列大麻类化合物，包括大麻中的精神活性成分β-9-四氢大麻酚(THC)、大麻素CB1受体拮抗剂利莫那班和AM251、以及AM4113、内源性大麻素类ANANDAME和2AG、非大麻类脂肪酸酰胺OEA和PEA、ANANDAM摄取抑制剂AM404和脂肪酸酰胺水解酶(FAAH)抑制剂URB597。对甲基苯丙胺、可卡因和海洛因的研究也在进行中。 内源性大麻素参与了人们刚刚开始了解的各种行为和生理过程。脂肪酸酰胺水解酶(FAAH)的抑制剂在大脑中自然释放时，会增加内源性ANANDAME(一种大麻类CB1受体配体)以及油酰乙醇胺和棕榈酰乙醇胺(OEA和PEA，a型过氧体增殖剂激活的核受体，PPAR-α)的水平。在大鼠的被动回避任务中，我们发现FAAH抑制剂URB597或PPAR-α激动剂WY14643可增强记忆获得，而这些增强可被PPAR-α拮抗剂MK886阻断。这些发现展示了通过激活PPAR-α来增强记忆的新机制，或者直接通过给予PPAR-α激动剂，或者间接通过给予FAAH抑制剂。 在五个选择的系列反应时间任务中，外源性大麻素已被发现能改变注意力，但内源性大麻素如双胺还没有被研究过。我们利用这项任务来评估阿南达胺对大鼠的影响。由于花环胺不仅是大麻素受体的配基，而且还是瞬时受体潜在香草素1(TRPV1)受体的配体，而且正如最近所建议的那样，过氧酶体增殖物激活的核受体(PPAR)，我们还确定了花环酰胺在这项任务中的作用是否都是由这些受体介导的。在试验间歇期间，阿南达胺增加了遗漏错误，减少了反应。这些作用可被TRPV1拮抗剂卡萨西平阻断，但不能被大麻素受体拮抗剂利莫那班或PPAR-α拮抗剂MK886阻断。在同一组大鼠身上进行的野外活动和食物消耗程序测试表明，在注意任务中观察到的操作型反应的中断不是由于运动抑制、焦虑、食欲下降或无法找到和食用食物颗粒。因此，阿南达胺引起的依赖香草素的行为干扰是操作性注意任务所特有的。双胺的这些作用类似于全身给药的多巴胺拮抗剂，可能反映了香草胺介导的多巴胺传递的变化。 FAAH酶是治疗焦虑症相关疾病的有希望的靶点。FAAH抑制剂(例如，URB597)增加了啮齿动物大脑中ANANDAME的水平，并诱导了类焦虑的作用。然而，由于不同实验室的发现不一致，最近的发现质疑FAAH抑制剂作为抗焦虑药物的有效性。我们在这里测试了一种假设，即相互矛盾的发现是由于在各种研究中使用的实验条件的压力大小不同造成的。我们发现，URB597不会产生缓解焦虑的效果，当测试程序的厌恶最小化时，通过在实验前每天处理老鼠，通过让它们习惯于实验室，或者在测试过程中使用低照度。相反，当通过消除对实验室的习惯性或使用明亮的照明条件来增加测试环境的厌恶时，URB597具有强大的焦虑缓解作用。与URB597不同的是，苯二氮卓酮(5 mg/kg)在所有测试条件下都具有抗焦虑作用。URB597的抗焦虑作用可被大麻素CB1受体拮抗剂AM251所阻断，表明URB597的抗焦虑作用是由CB1受体介导的。我们的研究结果表明，抑制FAAH在轻度压力环境下不会影响焦虑，但可以防止厌恶刺激产生焦虑的影响。

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.