Drugs On Learned & Spontaneous Behavior Of Experimental Animals

药物学习

• 批准号: 8336414
• 负责人: Steven Goldberg
• 金额: $ 97.96万
• 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/8336414
• 关键词: AM 251; AM404; Address; Adenosine A1 Receptor; Adverse effects; Agonist; Alzheimer' s Disease; Amides; Animals; Anxiety; Attention; Attenuated; Behavior; Behavior Control; Behavioral; Behavioral Mechanisms; Brain; CNR1 gene; Caffeine; Cannabinoids; Cannabis; Clinical; Cocaine; Cognition; Complement; Corpus striatum structure; Dependence; Desire for food; Development; Discrimination; Dopamine; Dopamine Antagonists; Dopaminergic Cell; Dose; Drug abuse; Emotional; Emotions; Endocannabinoids; Exposure to; Fatty Acids; Food; Glutamates; Goals; Heroin; Hippocampus (Brain); Infusion procedures; Intravenous; Learning; Ligands; Marijuana; Mediating; Memory; Memory impairment; Mental Depression; Methamphetamine; Microdialysis; Midbrain structure; Modeling; Molecular; Monkeys; Motor; Neurons; Nicotine; Nuclear Receptors; Nucleus Accumbens; Pattern; Performance; Peroxisome Proliferators; Pharmaceutical Preparations; Physiological Processes; Positioning Attribute; Procedures; Purinergic P1 Receptors; Rattus; Reaction Time; Research; Rodent Model; Self Administration; Series; Short-Term Memory; Signal Transduction; Stimulus; Testing; Tetrahydrocannabinol; Therapeutic; Tobacco; Tobacco smoking; Transgenic Organisms; Vanilloid; Ventral Tegmental Area; addiction; anandamide; cannabinoid receptor; capsazepine; design; drug discrimination; drug of abuse; drug reinforcement; drug reward; extracellular; fatty acid amide hydrolase; food consumption; in vivo; inhibitor/antagonist; memory acquisition; memory process; neurobiological mechanism; neurochemistry; novel; oleoylethanolamide; palmidrol; peroxisome; presynaptic; receptor; rehearsal; research study; response; rimonabant; transmission process; uptake; vanilloid receptor subtype 1

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, caffeine 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 previously 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.Experiments are continuing using transgenic Alzheimer's disease rodent models. Cannabis and caffeine are two of the most widely used psychoactive substances. THC, the main psychoactive constituent of cannabis, is known to produce deficits in short term memory. Caffeine, a non-selective adenosine receptor antagonist, attenuates some kinds of memory deficits, but there have been few studies addressing the effects of caffeine and THC in combination. Rats were given THC along with either caffeine or the selective adenosine A1-receptor antagonist CPT and tested with a delayed nonmatching-to-position procedure in which behavior during the delay is automatically recorded as a model of memory rehearsal. THC alone produced dose-dependent memory deficits. The initial exposure to caffeine disrupted the established pattern of rehearsal-like behavior, but tolerance developed rapidly to this effect. Caffeine and CPT alone had no significant effects on rehearsal or memory in subsequent testing. When a subthreshold dose of THC was combined with caffeine or CPT, memory performance was significantly decreased, even though performance of the rehearsal-like pattern was not significantly altered. Caffeine and CPT did not counteract memory deficits induced by THC, but in fact exacerbated them. These results are consistent with recent findings that adenosine receptors modulate cannabinoid signaling in the hippocampus. In other experiments using a five-choice serial reaction time task,the effects of the endocannabinoid anandamide were studied. 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 anandamide's 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. A common molecular mechanism contributing to the development of addiction that is shared by drugs of abuse(including cannabinoids) is their ability to increase levels of extracellular dopamine in the shell of the nucleus accumbens, but the underlying mechanisms have not yet been well established. Although cannabinoid CB1 receptors in the ventral tegmental area (VTA) have been suggested to be involved, in vivo administration of THC directly into the VTA does not induce dopamine release in the nucleus accumbens shell, while direct infusion of THC in the nucleus accumbens shell does. It has been suggested that presynaptic CB1 receptors that control striatal glutamate release are main targets for the dopamine-releasing effects of cannabinoids by decreasing excitability of striatal GABAergic dynorphinergic neurons that project to the mesencephalon and tonically inhibiting dopaminergic cells in the VTA. Presynaptic A2A receptors localized in striatal glutamatergic terminals could be responsible for the counteracting effects of the A2A receptor antagonist on the reinforcing effects of cannabinoids we found in parallel studies of intravenous THC self administration behavior. In that case, A2A receptor antagonists should also counteract THC-induced, but not cocaine-induced, dopamine release in the nucleus accumbens shell. Using in vivo microdialysis in freely moving rats, we found that a behaviorally active dose of MSX-3 significantly counteracted THC-induced increases in extracellular dopamine levels in the nucleus accumbens shell induced by THC. These effects of MSX-3 were selective, occurring with cannabinoids but not with cocaine.Further findings that the A2A receptor antagonist was able to reduce cannabinoid-induced self administration as well as dopamine release yet failed to attenuate cannabinoid-induced reinstatement of THC-seeking behavior in abstinent subjects reinforces the hypothesis that different mechanisms and brain circuits are involved in these phenomena; that dopamine is involved in cannabinoid self-administration, but its involvement in the reinstatement of cannabinoid drug-seeking may not be as pronounced.

正在进行的实验旨在评估由药物控制的行为背后的不同神经药理学和行为机制，作为大鼠和猴子的歧视性刺激，以及药理学或行为操纵改变歧视的能力，以及自我施用THC或尼古丁，破坏持续的食物维持行为，改变焦虑等情绪反应或调节注意力学习和记忆过程。目前，研究重点集中在尼古丁、咖啡因和一系列大麻素，包括大麻中的精神活性成分δ-9-四氢大麻酚（THC）、大麻素CB1受体拮抗剂利莫那班和AM251、内源性大麻素anandamide AM4113和非大麻素脂肪酸2AG 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 URB597。还对甲基苯丙胺、可卡因和海洛因进行研究。 内源性大麻素涉及多种行为和生理过程，人们刚刚开始了解这些过程。脂肪酸酰胺水解酶 (FAAH) 抑制剂在大脑中自然释放时，会增加 anandamide（大麻素 CB1 受体配体）、油酰乙醇酰胺和棕榈酰乙醇酰胺（OEA 和 PEA，a 型过氧化物酶体增殖物激活核受体 PPAR-α 的配体）的内源水平。通过对大鼠进行被动回避任务，我们之前发现 FAAH 抑制剂 URB597 或 PPAR-α 激动剂 WY14643 增强了记忆获取，而这些增强被 PPAR-α 拮抗剂 MK886 阻断。这些发现证明了通过直接施用PPAR-α激动剂或间接施用FAAH抑制剂来激活PPAR-α来增强记忆的新机制。使用转基因阿尔茨海默氏病啮齿动物模型的实验正在继续进行。 大麻和咖啡因是两种最广泛使用的精神活性物质。 THC 是大麻的主要精神活性成分，已知会导致短期记忆缺陷。咖啡因是一种非选择性腺苷受体拮抗剂，可以减轻某些类型的记忆缺陷，但很少有研究探讨咖啡因和 THC 联合使用的影响。 给大鼠服用 THC 和咖啡因或选择性腺苷 A1 受体拮抗剂 CPT，并使用延迟的非匹配位置程序进行测试，其中延迟期间的行为被自动记录为记忆排练的模型。单独使用 THC 会产生剂量依赖性记忆缺陷。最初接触咖啡因破坏了既定的排练行为模式，但对此的耐受性迅速发展。在随后的测试中，单独使用咖啡因和 CPT 对排练或记忆没有显着影响。当阈下剂量的 THC 与咖啡因或 CPT 结合使用时，记忆表现显着下降，尽管排练样模式的表现没有显着改变。咖啡因和喜树碱并不能抵消四氢大麻酚引起的记忆缺陷，事实上反而加剧了它们。这些结果与最近的发现一致，即腺苷受体调节海马中的大麻素信号传导。在其他使用五选择串行反应时间任务的实验中，研究了内源性大麻素 anandamide 的作用。由于 anandamide 不仅是大麻素受体的配体，而且还是瞬时受体电位香草酸 1 (TRPV1) 受体的配体，以及最近提出的过氧化物酶体增殖物激活核受体 (PPAR)，因此我们还确定了 anandamide 在这项任务中的作用是否是由这些受体介导的。 Anandamide 增加了试验间隔期间的遗漏错误并降低了响应。这些作用可以被 TRPV1 拮抗剂辣椒西平阻断，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。对同一只老鼠的旷场活动和食物消耗程序进行的测试表明，在注意力任务中观察到的操作反应的破坏并不是由于运动抑制、焦虑、食欲下降或无法找到和消耗食物颗粒造成的。因此，由 anandamide 引起的香草素依赖性行为干扰是操作性注意力任务所特有的。 anandamide 的这些作用类似于全身施用多巴胺拮抗剂的作用，并且可能反映了香草酸介导的多巴胺传递的变化。 滥用药物（包括大麻素）所共有的导致成瘾的一个常见分子机制是它们能够增加伏隔核壳中细胞外多巴胺的水平，但其潜在机制尚未明确。尽管腹侧被盖区 (VTA) 的大麻素 CB1 受体被认为参与其中，但在体内将 THC 直接注入 VTA 不会诱导伏隔核壳中多巴胺的释放，而直接将 THC 输注到伏隔核壳中则会引起多巴胺释放。有人认为，控制纹状体谷氨酸释放的突触前 CB1 受体是大麻素释放多巴胺作用的主要目标，通过降低投射到中脑的纹状体 GABA 强啡能神经元的兴奋性并强直性抑制 VTA 中的多巴胺能细胞。我们在静脉内 THC 自我给药行为的平行研究中发现，位于纹状体谷氨酸能末端的突触前 A2A 受体可能是 A2A 受体拮抗剂对大麻素增强作用的抵消作用的原因。在这种情况下，A2A 受体拮抗剂还应该抵消 THC 诱导的伏核壳中多巴胺的释放，但不能抵消可卡因诱导的多巴胺释放。在自由活动的大鼠中使用体内微透析，我们发现行为活性剂量的 MSX-3 显着抵消了 THC 诱导的伏核壳中细胞外多巴胺水平的增加。 MSX-3 的这些作用是选择性的，在大麻素中发生，但在可卡因中则不然。进一步的发现表明，A2A 受体拮抗剂能够减少大麻素诱导的自我给药以及多巴胺释放，但无法减弱大麻素诱导的戒断受试者 THC 寻求行为的恢复，这强化了以下假设：不同的机制和大脑回路参与了这些作用。 现象；多巴胺参与大麻素的自我给药，但它对恢复大麻素药物寻求的参与可能不那么明显。