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The role of GPER-1 and addiction

GPER-1 的作用和成瘾

基本信息

批准号：
10455025
负责人：
JILL B. BECKER
金额：
$ 32.44万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2020-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455025
关键词：
Acute Adolescence Adolescent Adult Affect Agonist Animals Aromatase Attenuated Behavior Binding Biological Brain Characteristics Chronic Cocaine Complex Corpus striatum structure Data Development Dopamine Dorsal Dose Drug Targeting Drug usage Enzymes Estradiol Estrogen Receptor alpha Estrogen Receptor beta Female GTP-Binding Proteins Goals Gonadal Hormones Hormone Receptor Hormones Human Illicit Drugs Lead Measures Mediating Microdialysis Modeling Motivation Nature Ovary Pharmaceutical Preparations Population Prevalence Prevention Prevention approach Property Public Health RBM5 gene Raloxifene Rattus Receptor Activation Relapse Rewards Rodent Model Role Schedule Self Administration Sex Differences Site Substance Use Disorder Taste preferences Testing Testis Testosterone Work addiction aged antagonist G conditioned place preference evidence base experimental study illicit drug use male neurobiological mechanism neurotransmission novel preference protective effect psychostimulant receptor relating to nervous system response sex targeted treatment

项目摘要

Project Summary/Abstract Addiction is a major public health concern. Approximately 8.3% of the population needed treatment for addiction in 2013. Cocaine is one commonly used illicit drug that is abused by 10-12% of the population and is highly addictive. During adolescents, equivalent numbers of males and females are abusing or dependent on cocaine. In adults aged 18 and older, the prevalence is double in males compared to females. It is important that we identify why twice as many males are continuing to use after adolescence, and identify novel potential treatment targets that can be beneficial to males. While our lab has historically studied sex differences and especially the characteristics of female drug taking, the studies proposed focus on a novel mechanism that may mitigate drug taking in males. In the proposed work, we investigate a novel mechanism through which the preference and motivation for cocaine is differentially affected in males, but not females. Estradiol (E2) is an important hormone in the brains of both females and males. In males, E2 in the brain is synthesized from testosterone via the enzyme aromatase. In both sexes, E2 acts by binding to one of three types of E2 receptors (ER)s: alpha (α), beta (β), or G-protein receptor -1 (GPER-1). Previous studies have found that E2 potentiates cocaine-induced DA in the dorsal striatum (dSTR) and enhances acquisition of drug taking in females only. The studies proposed will identify how ER activation of GPER-1 differentially influences preference and motivation for cocaine in male and female rats. Our preliminary data show that activation of GPER-1 in the dSTR of male rats blocks conditioned place preference (CPP) for cocaine, but has no effect on CPP in females. Additional preliminary results find that activating GPER-1 attenuates cocaine-induced DA increases within the dSTR of males, but not females. Together, these results suggest that GPER-1 activation may have a protective effect against the rewarding effects of cocaine in male rats, but not females. The experiments proposed will investigate: 1) whether sex differences in GPER-1 receptor activation in the dSTR are related to the preference for cocaine; 2) the effect of GPER-1 on cocaine-induced DA release in male and female rats; and 3) the effect of GPER-1 on the motivation for cocaine in male and female rats during acquisition and after acquisition. Addiction treatment needs targeted treatment for males and females. This work will open new avenues for prevention and treatment of addiction by providing a sex-specific understanding of gonadal hormones the neurobiological mechanisms mediating the rewarding properties of psychostimulants.

项目总结/文摘