Mechanisms Mediating Cocaine Abuse in Socially Housed Female and Male Monkeys

社会饲养的雌性和雄性猴子中调节可卡因滥用的机制

基本信息

批准号：
10765789
负责人：
Michael A Nader
金额：
$ 12.24万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10765789
关键词：
Acute Affect American Animal Model Animals Behavior Behavioral Brain Chronic Cocaine Cocaine Abuse Cocaine Dependence Cognition Development Dopamine Drug Addiction Drug Modulation Drug abuse FDA approved Female Food Funding Glucose Goals Human Impulsivity Individual Differences Intravenous Long-Term Effects Macaca fascicularis Maintenance Measures Mediating Modeling Monkeys Neurobiology Outcome Performance Pharmaceutical Preparations Pharmacotherapy Positron-Emission Tomography Public Health Raclopride Reporting Research Research Project Grants Self Administration Social Hierarchy Treatment outcome Work cocaine self-administration cocaine use cognitive performance fluorodeoxyglucose individualized medicine kappa opioid receptors male non-drug nonhuman primate novel personalized medicine pharmacologic pre-clinical preference receptor reinforcer response sex social social factors treatment strategy

项目摘要

Drug abuse continues to be a major public health problem worldwide, with over 1.5 million Americans confirming current cocaine use and, at present, there are no FDA-approved treatments for cocaine addiction. This research project is a continuation of funded work aimed at understanding the neurobiology of cocaine abuse in a unique nonhuman primate model: intravenous cocaine self-administration in socially housed cynomolgus monkeys. The goals of the present application are to continue using this homologous animal model to examine the mechanisms of action mediating the interactions between social hierarchy and environmental and pharmacological modulation of drug self-administration in female and male monkeys. Over the previous funding period, we have noted sex- and social-rank related differences in vulnerability to cocaine self-administration (SA) and in response to several acute pharmacological manipulations. In Aim 1, we will extend this characterization to chronic drug treatment in socially housed monkeys self-administering cocaine in the context of an alternative, non-drug, reinforcer (food-cocaine choice). We will also examine how these treatments affect cocaine-induced reinstatement. The studies in Aim 2 will extend these sex- and social-rank differences to impulsive-like behavior by implementing delays to food and cocaine. When food is delayed, we hypothesize that females will be more “impulsive” compared to males and when cocaine is delayed, subordinates will require longer delays to shift preference. The effects of long-term cocaine SA and chronic drug treatment on cognitive performance in socially housed monkeys will be examined in Aim 3. We hypothesize that cognitive performance of females will be more disrupted by cocaine than performance by males and that subordinate monkeys will be more sensitive than dominant animals. We have reported social- rank related differences in brain glucose utilization using [18F]fluorodeoxyglucose and PET and in dopamine D2/D3 receptor availability using [11C]raclopride and most recently in kappa opioid receptor availability using [11C]ECAP. The goal of Aim 4 is to examine how cocaine SA and chronic drug treatment differentially affects these measures in socially housed female and male monkeys. The scientific premise is that different mechanisms maintain cocaine SA based on social rank and sex and thus different drugs will be required to produce a positive outcome in these groups. We are proposing a preclinical personalized-medicine strategy for treating drug abuse that incorporates sex and social variables. Results from these studies should aid in the development of novel and individualized treatment strategies for drug addiction.

药物滥用仍然是全球主要的公共卫生问题，超过 150 万美国人确认目前可卡因的使用情况，目前尚无 FDA 批准的可卡因成瘾治疗方法。该研究项目是旨在了解可卡因神经生物学的资助工作的延续独特的非人类灵长类动物模型中的滥用：社会安置中的静脉注射可卡因自我给药本申请的目标是继续使用这种同源动物。模型来研究调节社会等级和等级之间相互作用的行动机制雌性和雄性猴子自我给药的环境和药理调节。在上一个资助期间，我们注意到可卡因脆弱性与性别和社会等级相关的差异在目标 1 中，我们将进行自我给药 (SA) 和对几种急性药理学操作的反应。将这一特征扩展到社会饲养的猴子的慢性药物治疗中，这些猴子自我施用可卡因我们还将研究如何使用替代的非药物强化剂（食物可卡因选择）。治疗会影响可卡因引起的恢复。目标 2 中的研究将扩大这些性别和社会等级。通过延迟进食和可卡因来区别冲动行为。重点是，与男性相比，女性会更“冲动”，并且当可卡因延迟时，下属需要更长的时间才能改变偏好。长期可卡因 SA 和慢性可卡因的影响。药物治疗对社会饲养的猴子认知表现的影响将在目标 3 中进行研究。我们最近，可卡因对女性认知能力的干扰程度高于可卡因对女性认知能力的干扰程度雄性和从属猴子会比占主导地位的动物更敏感。使用 [18F] 氟脱氧葡萄糖和 PET 以及多巴胺对脑葡萄糖利用的排名相关差异使用[11C]雷氯必利的 D2/D3 受体可用性以及最近使用的 kappa 阿片受体可用性 [11C]ECAP 目标 4 的目标是研究可卡因 SA 和慢性药物治疗的不同影响。这些措施在社会饲养的雌性和雄性猴子中的科学前提是不同的。机制根据社会等级和性别维持可卡因SA，因此需要不同的药物来维持可卡因SA 我们正在为这些群体提出一种临床前个性化医疗策略。这些研究的结果应该有助于结合性别和社会变量来治疗药物滥用。开发新颖的个体化药物成瘾治疗策略。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Comparison of rectal and infrared thermometry for obtaining body temperature in cynomolgus macaques (Macaca fascicularis).

直肠测温法和红外测温法获取食蟹猴体温的比较。

DOI：
发表时间：
2007-12
期刊：
影响因子：
0.7
作者：
Sikoski, P;Banks, M L;Gould, R;Young, R W;Wallace, J M;Nader, M A
通讯作者：
Nader, M A

Time to connect: bringing social context into addiction neuroscience.

是时候联系了：将社会背景带入成瘾神经科学。

DOI：
发表时间：
2016-09
期刊：
影响因子：
0
作者：
Heilig, Markus;Epstein, David H;Nader, Michael A;Shaham, Yavin
通讯作者：
Shaham, Yavin

Effects of social reorganization on dopamine D2/D3 receptor availability and cocaine self-administration in male cynomolgus monkeys.

社会重组对雄性食蟹猴多巴胺 D2/D3 受体可用性和可卡因自我给药的影响。

DOI：
发表时间：
2017-09
期刊：
影响因子：
3.4
作者：
Czoty, P W;Gould, R W;Gage, H D;Nader, M A
通讯作者：
Nader, M A

Effects of the α-2 Adrenergic Receptor Agonists Lofexidine and Guanfacine on Food-Cocaine Choice in Socially Housed Cynomolgus Monkeys.

α-2 肾上腺素能受体激动剂洛非西定和胍法辛对社会饲养食蟹猴食物可卡因选择的影响。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Czoty, Paul W;Nader, Michael A
通讯作者：
Nader, Michael A

Nonhuman primate models of social behavior and cocaine abuse.

非人类灵长类动物的社会行为和可卡因滥用模型。

DOI：
发表时间：
2012-11
期刊：
影响因子：
3.4
作者：
Nader, Michael A;Czoty, Paul W;Nader, Susan H;Morgan, Drake
通讯作者：
Morgan, Drake

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Michael A Nader其他文献

Cognitive performance as a behavioral phenotype associated with cocaine self-administration in female and male socially housed monkeys.

认知表现作为一种行为表型，与雌性和雄性社会饲养的猴子的可卡因自我给药相关。

DOI：
10.1038/s41386-024-01882-7
发表时间：
2024-05-17
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
0
作者：
Mia I. Allen;Marissa B Costa;Bernard N Johnson;Robert W Gould;Michael A Nader
通讯作者：
Michael A Nader