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Role of dopamine D3 and serotonin 2C receptors in the development of an addiction-like phenotype in rats

多巴胺 D3 和血清素 2C 受体在大鼠成瘾样表型发展中的作用

基本信息

批准号：
10217088
负责人：
Michelle Riane Doyle
金额：
$ 5.4万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217088
关键词：
Agonist Behavior Behavioral Binding Cessation of life Cocaine Development Dopamine Drug usage Effectiveness Epidemic Exhibits FDA approved Female Future Individual Differences Infusion procedures Intake Measures Mediating Modeling Motivation Neurobiology Neuronal Plasticity Norepinephrine Overdose Pattern Pharmaceutical Preparations Pharmacotherapy Phenotype Play Public Health Punishment Quantitative Autoradiography Rattus Recording of previous events Reporting Research Research Project Grants Role Self Administration Serotonin Serotonin Receptor 5-HT2C Severities Shock Signal Transduction Substance Use Disorder System Testing Time United States Yawning addiction adverse outcome base bath salts behavioral pharmacology cocaine self-administration dopamine D3 receptor foot male neurochemistry novel pramipexol receptor receptor density receptor expression receptor function response serotonin transporter sex stimulant use disorder uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Rates of substance use disorders (SUDs) and deaths by drug overdose in the United States have reached epidemic levels; yet, the behavioral, pharmacological, and neurobiological determinants of one’s vulnerability to develop a substance use disorder are not well understood. A variety of behavioral and neurochemical phenotypes are thought to predispose rats to developing addiction-like phenotypes based on the following criteria: (1) difficulty stopping drug use; (2) high motivation to take the drug; and, (3) continued drug-taking despite adverse consequences. Though a number of studies suggest that a subset of rats will develop these addiction-like behaviors following long- or intermittent-access to cocaine self-administration, it is important to note that this conceptual framework does not incorporate a core feature of SUDs, high levels of dysregulated drug intake. Indeed, when rats self-administer cocaine under short-access conditions, drug intake tends to be well-regulated, with little inter-subject variability. Conversely, when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV; a synthetic cathinone that selectively inhibits uptake at dopamine and norepinephrine relative to serotonin transporters) under short-access conditions, ~40% of them (i.e., “high-responders”) develop unusually high levels of drug intake (i.e., ~3-fold greater than “low-responders”). Early studies also suggest that “high-responders” exhibit high rates of responding during periods of signaled drug unavailability (e.g., drug-seeking), earn more infusions under a progressive ratio (e.g., increased motivation), and are less sensitivity to punishment by foot shock (e.g., continue drug-taking despite adverse consequences). In addition to recapitulating the addiction-like phenotype often reported with long- or intermittent-access to cocaine, because MDPV self-administration also reliably establishes high levels of dysregulated drug-taking, a core feature of addiction, we believe that our model provides a novel and robust approach to study the factors that impact one’s vulnerability to develop a SUD. For instance, mounting evidence suggests that high levels of drug intake and addiction-like patterns of drug taking can result in more robust neuroplastic changes in dopamine (e.g., increases in dopamine D3 receptors) and serotonin (e.g., decreases in serotonin2C receptors) systems that are known to play key roles in mediating the reinforcing effects of drugs. The research project aims to utilize IV self-administration in rats to 1) determine the impact of short-, long-, and intermittent access to MDPV on the development of addiction-like phenotypes in male and female rats; and 2) determine whether the relationship between the dopamine D3 and serotonin2C receptors (expression and function) and the development or severity of addiction-like phenotypes varies as a function of drug (MDPV or cocaine), access condition (short-, long-, intermittent-access), and/or sex. Together, these studies will provide essential information about the causal role of dopamine D3 and serotonin2C receptors and the development or manifestation of dysregulated drug-taking behavior.

项目总结/文摘

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

3,4-Methylenedioxypyrovalerone High-Responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder.

3,4-亚甲基二氧基吡咯戊酮高反应表型作为评估兴奋剂使用障碍候选药物的工具。

DOI：
10.1124/jpet.122.001419
发表时间：
2023
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
0
作者：
Doyle,MichelleR;Peng,LindseyN;Cao,Jianjing;Rice,KennerC;Newman,AmyHauck;Collins,GregoryT
通讯作者：
Collins,GregoryT

MDPV self-administration in female rats: influence of reinforcement history.

DOI：
10.1007/s00213-020-05726-2
发表时间：
2021-03
期刊：
Psychopharmacology
影响因子：
3.4
作者：
Doyle MR;Sulima A;Rice KC;Collins GT
通讯作者：
Collins GT

Evaluating Compulsive-Like Drug-Taking Using Signaled and Unsignaled Footshock Procedures in Male and Female Rats Self-Administering MDPV.

使用信号和无信号足部电击程序评估雄性和雌性大鼠自我管理 MDPV 的强迫性吸毒行为。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Doyle,MichelleR;Peng,LindseyN;Rice,KennerC;Collins,GregoryT
通讯作者：
Collins,GregoryT

Interactions between impulsivity and MDPV self-administration in rats.