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Neurobiology of Female Sexual Desire

女性性欲的神经生物学

基本信息

批准号：
9753686
负责人：
Robert L Meisel
金额：
$ 32.73万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753686
关键词：
Age Animal Model Arousal Behavior Behavioral Chemosensitization Clinical Conflict (Psychology)Dendritic Spines Development Disease Distress Dopamine Dopamine D1 Receptor Drug Approval Elements Eye Failure Female GTP-Binding Proteins Glutamates Goals Hamsters Individual Link Literature MAP kinase activator MAPK3 gene Measures Mediating Mesocricetus auratus Mitogen-Activated Protein Kinases Modeling Molecular Molecular Target Morphology Motivation Neurobiology Neurons Neurotransmitters Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Pharmacology Phosphorylation Pre-Clinical Model Prefrontal Cortex Prevalence Procedures Process Property Reporting Research Rewards Rodent Severities Sex Behavior Sexual Arousal Sexual Dysfunction Signal Pathway Signal Transduction Signaling Protein Source Spouses Structure Testing Therapeutic Translating Viral Woman base behavioral plasticity density design designer receptors exclusively activated by designer drugs drug development effective therapy experience feeding interest male mesolimbic system molecular targeted therapies novel pre-clinical preference pressure prevent public health relevance relating to nervous system reproductive self esteem sexual debut therapeutic development therapeutic target willingness

项目摘要

DESCRIPTION Sexual dysfunction in women is primarily characterized by low levels of sexual arousal and desire. Because no effective treatments exist for disorders of sexual desire in women, the FDA was pressured to fast-track approval for the drug Addyi despite the absence of clinical evidence that the drug provided any therapeutic benefit. Underlying the inability to construct a rational approach to developing therapeutics for disorders of sexual desire in women is the lack of research on the mechanistic basis for female sexual desire in pre-clinical models. We have developed a Syrian hamster model of sexual desire that captures several essential elements needed to translate the findings to women. We developed a procedure to evaluate the rewarding properties of female sexual behavior, an element reported to be lacking in women with low sexual desire. Women with low sexual desire also do not initiate sexual contacts with their spouse or partner. In this regard we discovered an experimental approach to test the female hamster's willingness to initiate sexual contacts with a male. Based on these hamster studies we demonstrated that the rewarding consequences of sexual interactions with a male feed forward to increase the female's sexual contacts. We further identified the mesolimbic dopamine system, and prefrontal glutamatergic afferents, centered on the nucleus accumbens, as a critical neural node mediating the rewarding effects of sexual behavior in females. The research in this proposal takes three specific approaches to establish a programmatic understanding of the neurobiology of female sexual desire. In the first aim we will use inhibitory DREADDs to determine the relative contribution of dopamine and glutamate afferents to the nucleus accumbens to the development of sexual reward and initiation of sexual interactions with the male in our hamster model. We will also examine the contributions of these afferents to changes in dendritic spine morphology consequent to female sexual experience. The second aim takes a discovery approach to examining three possible intracellular signaling pathways mediating the effects of sexual experience on behavioral and morphological plasticity. The last aim will pharmacologically manipulate the individual signaling pathways to identify which of these pathways are potential molecular targets for therapeutic development to treat problems of sexual desire in women. Collectively this research will take a systematic approach to developing a neurobiology of female sexual desire with an eye to the rational development of effective therapies.

描述