Drugs On Learned & Spontaneous Behavior Of Experimental Animals

药物学习

• 批准号: 8736705
• 负责人: Steven Goldberg
• 金额: $ 80.81万
• 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/8736705
• 关键词: Acute; Adverse effects; Affect; Agonist; Animals; Anxiety; Attention; Bathing; Behavior; Behavior Control; Behavioral; Behavioral Mechanisms; Binge Eating; Binge eating disorder; Biological Assay; Body Weight; Brain; Butyrylcholinesterase; CNR1 gene; CNR2 gene; Cannabinoids; Cardiovascular system; Catecholamines; Cells; Characteristics; Chronic; Clinical; Cocaine; Cocaine Abuse; Cocaine Dependence; Cognition; Complement; Corpus striatum structure; Data; Dependence; Dietary Fats; Discrimination; Disease; Dopamine; Dose; Drug Kinetics; Drug abuse; Drug usage; Eating; Eating Behavior; Emotional; Emotional disorder; Emotions; Endocannabinoids; Enzymes; Feeding behaviors; Female; Food; Functional disorder; Goals; Half-Life; Homeostasis; Hour; Human; Hypertension; In Vitro; Intake; Intravenous; Learning; Margarine; Marijuana; Measures; Mental Depression; Metabolic; Methamphetamine; Methods; Modeling; Molecular; Monkeys; Motor Activity; Mus; Mutation; Nicotine; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Plasma; Predisposition; Preparation; Psyche structure; Psychotropic Drugs; Public Health; Rattus; Relapse; Research; Rodent; Role; Saimiri; Salts; Scanning; Self Administration; Series; Signal Transduction; Slice; Source; Stimulus; Synaptosomes; Tachycardia; Tail; Techniques; Testing; Tetrahydrocannabinol; Therapeutic; Time; Tobacco; Tobacco smoking; Toxic effect; Water; aversive conditioning; base; behavior influence; cathinone; coping; design; drug discrimination; drug of abuse; drug reinforcement; drug reward; ecgonine methyl ester; extracellular; fatty acid amide hydrolase; in vivo; inhibitor/antagonist; learned behavior; man; memory process; monoamine; neurobiological mechanism; neurochemistry; neuroregulation; prevent; research study; resilience; response; rimonabant; stress related disorder; subcutaneous; transmission process; uptake

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 coacaine, nicotine and methamphetramine, and on a series of inhibitors of endocannabinoid uptake and metabolic breakdown. The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. We have evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods (Baumann et al., 2013). In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats. We found that MDPV blocks uptake of (3)Hdopamine (IC(50)=4.1 nM) and (3)Hnorepinephrine (IC(50)=26 nM) with high potency but has weak effects on uptake of (3)Hserotonin (IC(50)=3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats. Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations. Coping styles are fundamental characteristics of behavior that affect susceptibility to, and resilience during, mental and physical illness. Shifts from passive to active coping are considered therapeutic goals in many stress-related disorders, but the neural control of coping is poorly understood. Based on earlier findings, we hypothesized that coping styles are influenced by endocannabinoids. We have now tested whether FAAH inhibition by URB597 affects behaviors aimed at controlling a critical situation and the degree to which environmental stimuli influence behavior i.e., we studied the impact of URB597 on the two main attributes of coping styles (Haller et al., 2013). Rats were tested in the tail-pinch test of coping and in the elevated plus-maze test that was performed under highly divergent conditions. Under the effects of URB597, rats focused their behavior more on the discomfort-inducing clamp in the tail-pinch test, i.e., they coped with the challenge more actively. In the elevated plus-maze, URB597-treated rats demonstrated an autonomous behavioral control by reducing both "wariness" induced by aversive conditions and "carelessness" resulting from favorable conditions.Thus, URB597 treatment-induced behavioral changes indicated a shift towards active coping with challenges. This behavioral change appears compatible with the previously suggested role of endocannabinoids in emotional homeostasis. Although further studies are required to characterize the role of endocannabinoids in coping, these findings suggest that the enhancement of endocannabinoid signaling may become a therapeutic option in emotional disorders characterized by passive coping (e.g., anxiety and depression) and in physical diseases where active coping is therapeutically desirable. Binge eating disorder (BED) is characterized by excessive food intake during short periods of time. Recent evidence suggests that alterations in endocannabinoid signalling could be involved in the pathophysiology of BED. We have investigated whether pharmacological manipulation of endocannabinoid transmission may be effective in modulating the aberrant eating behaviour present in a validated rat model of BED (Scherma et al., 2013). Binge-type eating was induced in female rats by providing limited access to an optional source of dietary fat (margarine). Rats were divided into three groups, all with ad libitum access to chow and water: control (C), with no access to margarine; low restriction (LR), with 2 h margarine access 7 days a week; high restriction (HR), with 2 h margarine access 3 days a week. Compared with the LR group, the HR group consumed more margarine and this was accompanied by an increase in body weight. The cannabinoid CB1 /CB2 receptor agonist delta-9-tetrahydrocannabinol significantly increased margarine intake selectively in LR rats, while the fatty acid amide hydrolase inhibitor URB597 showed no effect. The CB1 receptor inverse agonist/antagonist rimonabant dose-dependently reduced margarine intake in HR rats. Notably, in HR rats, chronic treatment with a low dose of rimonabant induced a selective long-lasting reduction in margarine intake that did not develop tolerance, and a significant and persistent reduction in body weight. Chronic pharmacological blockade of CB1 receptors reduces binge eating behavior in female rats and may prove effective in treating BED, with an associated significant reduction in body weight. Substantial research has focused on developing pharmacological treatments for cocaine abuse but no effective medications have been developed. Enzymes that metabolize cocaine in the periphery and prevent its entry into the brain can prevent cocaine toxicity and its behavioral effects in rodents. We assessed the effects of one such enzyme (Albu-CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys (Schindler et al., 2013). Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic studies showed that Albu-CocH (5 mg/kg) had a relatively long half-life of 56.6 hours in squirrel monkeys. In these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced two hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hrs following Albu-CocH administration. Pretreatment with 5 mg/kg Albu-CocH also reduced cocaine self-administration and the discriminative stimulus effects of cocaine which suggests it may be effective in reducing cocaine addiction and relapse liability or in reversing acute cocaine toxicity in man.

正在进行实验，以评估在大鼠和猴子中，作为区别性刺激的药物控制的行为背后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区别的能力，以及四氢大麻酚和尼古丁的自我管理，破坏或调节食物维持的行为，改变焦虑等情绪反应，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的抑制剂。