Drugs On Learned & Spontaneous Behavior Of Experimental Animals

药物学习

• 批准号: 8933798
• 负责人: Steven Goldberg
• 金额: $ 60.31万
• 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/8933798
• 关键词: 3,4-Methylenedioxyamphetamine; Abstinence; Acute; Adrenergic Receptor; Adverse effects; Affect; Aggressive behavior; Aging; Anabolism; Animals; Anxiety; Attention; Attenuated; Bathing; Behavior; Behavior Control; Behavioral; Behavioral Mechanisms; Brain; Cannabinoids; Cardiovascular Physiology; Cardiovascular system; Cell Aging; Cell Cycle Regulation; Ceramides; Clinical; Cocaine; Cognition; Complement; Complex; Conscious; Coronary Arteriosclerosis; Cytochrome P450; Dependence; Deterioration; Development; Discrimination; Disease; Dose; Drug abuse; Drug usage; Effectiveness; Emotional; Emotions; Endocannabinoids; Enzymes; Feeding behaviors; Female; Food; Genetic Transcription; Goals; Health; Heart Rate; Hormonal; Hydroxyl Radical; Impulsivity; Inflammation; Lactation; Learning; Link; Marijuana; Maternal Behavior; Measures; Metabolic; Metabolism; Methamphetamine; Molecular; Molecular Mechanisms of Action; Monkeys; Motivation; Motor Activity; Nicotine; Nuclear; Organ; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Production; Propranolol; Psychotropic Drugs; Public Health; Rattus; Reactive Oxygen Species; Recruitment Activity; Research; Role; Salts; Self Administration; Self-Administered; Series; Social Behavior; Sphingolipids; Stimulus; Tachycardia; Techniques; Testing; Therapeutic; Tobacco; Tobacco smoking; Toxic effect; Vasopressins; Violence; adverse outcome; alpha methyldopamine; design; discounting; drug discrimination; drug of abuse; drug reinforcement; drug reward; ecstasy; experience; human tissue; improved; in vivo; inhibitor/antagonist; learned behavior; male; maternal aggression; memory process; methamphetamine abuse; neurobiological mechanism; neurochemistry; novel therapeutics; prevent; psychostimulant; research study; response; senescence; social; uptake; violent attack

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 and nicotine, to disrupt or modulate food-maintained behavior, to alter emotional responses such as anxiety and to modulate attention learning and memory processes. Currently, studies are focusing on constituents of psychoactive bath salts products, on cocaine, nicotine and methamphetamine, and on a series of inhibitors of endocannabinoid uptake and metabolic breakdown. The abuse of 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a growing public health concern The cardiovascular effects produced by MDMA contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. We examined the effects of MDMA metabolites on cardiovascular function in rats. Radiotelemetry was employed to evaluate the effects of s.c. administration of racemic MDMA and its phase I metabolites on BP, heart rate (HR) and locomotor activity in conscious male rats. MDMA (1-20 mgkg(-1)) produced dose-related increases in BP, HR and activity. The peak effects on HR occurred at a lower dose than peak effects on BP or activity. The N-demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), produced effects that mimicked those of MDMA. The metabolite 3,4-dihydroxymethamphetamine (HHMA; 1-10 mgkg(-1)) increased HR more potently and to a greater extent than MDMA, whereas 3,4-dihydroxyamphetamine (HHA) increased HR, but to a lesser extent than HHMA. Neither dihydroxy metabolite altered motor activity. The metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA) and 4-hydroxy-3-methoxyamphetamine (HMA) did not affect any of the parameters measured. The tachycardia produced by MDMA and HHMA was blocked by the β-adrenoceptor antagonist propranolol. Our results demonstrate that HHMA may contribute significantly to the cardiovascular effects of MDMA in vivo. As such, determining the molecular mechanism of action of HHMA and the other hydroxyl metabolites of MDMA warrants further study. The role of vasopressin in aggression has received much attention in recent years. However, vasopressin has complex roles on social behavior, which are affected by social experience, motivation and hormonal background, suggesting that its effects depend on the condition of subjects. This hypothesis was tested here by studying the impact of vasopressin deficiency on aggressiveness in reproductively naive and reproductively experienced males, as well as in lactating females, with special reference to the patterns and contexts of attack behavior. We also studied effects on impulsiveness, a behavioral feature strongly related to aggression. Vasopressin deficiency did not affect aggressiveness in reproductively experienced males, decreased the share of violent attacks in reproductively inexperienced males without affecting total attack counts, and suppressed maternal aggression in both early and late phases of lactation; violent forms of attack were decreased in the latter but not the former phase. Changes in aggression appeared unrelated to general changes in maternal behaviors. Impulsivity in the delay discounting task was markedly decreased by vasopressin deficiency in lactating females but not males. Taken together, our findings confirm that vasopressin has an impact on aggressiveness, but show that this impact depends on the condition of subjects, and suggest that the effects of vasopressin on maternal aggression develop in conjunction with impulsivity. Interestingly, overall effects on aggression and specific effects on violent attacks dissociated in both males and females, which hints to the possibility that vasopressin has distinct roles in the development of escalated forms of aggression. Methamphetamine is a highly addictive psychostimulant that causes profound damage to the brain and other body organs. Post mortem studies of human tissues have linked the use of this drug to diseases associated with aging, such as coronary atherosclerosis, but the molecular mechanism underlying these findings remains unknown. We have now found that methamphetamine accelerates cellular senescence and activates transcription of genes involved in cell-cycle control and inflammation by stimulating production of the sphingolipid messenger ceramide. This pathogenic cascade is triggered by reactive oxygen species, likely generated through methamphetamine metabolism via cytochrome P450, which recruit nuclear factors to induce expression of enzymes in the de novo pathway of ceramide biosynthesis. Inhibitors of ceramide formation prevent methamphetamine-induced senescence and attenuate systemic inflammation and health deterioration in rats self-administering the drug. The results suggest new therapeutic strategies to reduce the adverse consequences of methamphetamine abuse and improve effectiveness of abstinence treatments.

正在进行实验，以评估大鼠和猴子中作为辨别刺激的药物控制行为的不同神经药理学和行为机制，以及药理学或行为操纵改变THC和尼古丁的辨别以及自我给药的能力，以破坏或调节食物维持行为，改变情绪反应，如焦虑，并调节注意力、学习和记忆过程。目前，研究的重点是精神活性浴盐产品的成分、可卡因、尼古丁和甲基苯丙胺以及一系列内源性大麻素摄取和代谢分解抑制剂。 滥用3，4-亚甲二氧基甲基苯丙胺（MDMA;“迷魂药”）是一个日益严重的公共卫生问题。MDMA产生的心血管效应导致其急性毒性，但其代谢物在这些心血管效应中的潜在作用尚不清楚。我们研究了MDMA代谢产物对大鼠心血管功能的影响。采用无线电遥测技术评价s.c.给予外消旋摇头丸及其I相代谢物对清醒雄性大鼠的血压、心率（HR）和运动活动的影响。MDMA（1-20 mg kg（-1））使血压、心率和活动呈剂量相关性增加。对HR的峰值效应发生在低于对BP或活动的峰值效应的剂量下。N-去甲基化代谢物3，4-亚甲二氧基苯丙胺（MDA）产生的作用与MDMA相似。代谢物3，4-二羟基甲基苯丙胺（HHMA; 1-10 mg kg（-1））增加HR的作用更强，且程度大于MDMA，而3，4-二羟基苯丙胺（HHA）增加HR的作用，但程度小于HHMA。二羟基代谢物均未改变运动活性。代谢物4-羟基-3-甲氧基甲基苯丙胺（HMMA）和4-羟基-3-甲氧基苯丙胺（HMA）不影响任何测量参数。肾上腺素能受体拮抗剂心得安可阻断MDMA和HHMA引起的心动过速。我们的研究结果表明，HHMA可能有助于显着的心血管效应的MDMA在体内。因此，确定HHMA和MDMA的其他羟基代谢物的分子作用机制需要进一步研究。 近年来，加压素在攻击中的作用受到了广泛关注。然而，加压素对社会行为的作用是复杂的，它受到社会经验、动机和激素背景的影响，这表明它的作用取决于受试者的条件。这一假设是通过研究加压素缺乏对生殖幼稚和生殖经验丰富的男性以及哺乳期女性的攻击性的影响来验证的，特别是攻击行为的模式和背景。我们还研究了对冲动的影响，这是一种与攻击性密切相关的行为特征。加压素缺乏症并不影响侵略性的生殖经验丰富的男性，减少暴力攻击的比例在生殖经验不足的男性，而不影响总攻击计数，并抑制母亲的侵略性在早期和后期的哺乳期;暴力形式的攻击减少，在后者，但不是前一阶段。攻击性的变化似乎与母亲行为的一般变化无关。在延迟折扣任务中的冲动显着降低加压素缺乏的哺乳期女性，但男性。两者合计，我们的研究结果证实，加压素对侵略性的影响，但显示，这种影响取决于受试者的条件，并建议加压素对母亲的侵略性发展的影响与冲动。有趣的是，攻击的整体效果和暴力攻击的具体效果在男性和女性中分离，这暗示了加压素在攻击升级形式的发展中具有独特作用的可能性。 甲基苯丙胺是一种高度成瘾的精神兴奋剂，对大脑和其他身体器官造成严重损害。人体组织的尸检研究已经将这种药物的使用与衰老相关的疾病联系起来，例如冠状动脉粥样硬化，但这些发现背后的分子机制仍然未知。我们现在发现，甲基苯丙胺通过刺激鞘脂信使神经酰胺的产生，加速细胞衰老并激活参与细胞周期控制和炎症的基因的转录。这种致病性级联反应是由活性氧物质触发的，可能是通过细胞色素P450代谢甲基苯丙胺产生的，其募集核因子以诱导神经酰胺生物合成的从头途径中的酶的表达。神经酰胺形成抑制剂可预防甲基苯丙胺诱导的衰老，并减轻大鼠自我给药后的全身炎症和健康恶化。研究结果提出了新的治疗策略，以减少甲基苯丙胺滥用的不良后果，提高戒毒治疗的有效性。