A Role for the Preoptic Area in Modulating Cocaine Reward

视前区在调节可卡因奖赏中的作用

• 批准号: 8305371
• 负责人: Juan M Dominguez
• 金额: $ 30万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305371
• 关键词: Accident and Emergency department; Affect; Agonist; American; Androgen Receptor; Animal Model; Animals; Area; Attention; Behavior; Behavior Therapy; Behavioral; Behavioral Assay; Brain; Brain region; Cells; Cocaine; Cocaine Abuse; Cocaine Users; DSM-IV; Data; Dependence; Development; Dopamine; Drug Addiction; Drug abuse; Drug usage; Effectiveness; Endocrine; Epidemic; Estrogen Receptors; Female; Future; Gender; Gonadal Hormones; Health; Hormonal; Hormone Antagonists; Hormone Receptor; Hormones; Hypothalamic structure; Label; Lesion; Maternal Behavior; Medial; Mediating; Microdialysis; Microinjections; Nervous system structure; Neurobiology; Neurons; Neurosecretory Systems; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Pharmacological Treatment; Play; Population; Preoptic Areas; Prevention strategy; Process; Progesterone Receptors; Property; Rattus; Regulation; Rewards; Role; Sex Behavior; Sex Characteristics; Structure; Surveys; System; Testing; Ventral Tegmental Area; Visit; Woman; Work; addiction; aged; brain behavior; cocaine use; dopamine system; immunoreactivity; in vivo; male; meetings; men; neurochemistry; neuronal cell body; pre-clinical; preference; psychostimulant; receptor; research study; response; reward processing; therapy development; treatment strategy

DESCRIPTION (provided by applicant): Most studies point to the mesocorticolimbic dopamine (DA) system as the necessary neurobiological endpoint when describing cocaine's rewarding properties; however, this system does not operate in isolation, and input from other structures may play a significant role in cocaine reward. One area that has received little attention as a potential modulator of cocaine-induced activity is the medial preoptic area of the hypothalamus (MPOA). The MPOA is involved in the regulation of two naturally rewarding behaviors (maternal and sexual behaviors), is sexually dimorphic, and interacts with areas in the mesocorticolimbic system. As such, the MPOA is a logical candidate for a neuroanatomical locus modulating cocaine-induced activity, yet surprisingly little is known about the role of this structure in the context of drug abuse. Here, we focus on preclinical animal models of cocaine reward, hypothesizing that the MPOA modulates cocaine-induced activity in the mesocorticolimbic system and resulting behavioral expression of reward, including sex differences. The proposed studies will answer the following questions: (1) Does the MPOA modulate cocaine-induced neuronal and dopamine activity in the mesocorticolimbic system? (2) Does the MPOA modulate cocaine reward? (3) Do cells in the MPOA containing gonadal-hormone receptors interact with the mesocorticolimbic system? (4) Do gonadal hormones act via the MPOA to modulate cocaine-induced neuronal and dopamine activity in the mesocorticolimbic system? (5) Do gonadal hormones act via the MPOA to modulate cocaine reward? Using neuroanatomical, neurochemical, and behavioral assays, the proposed work will examine whether the MPOA may serve as an extension of the reward pathway in modulating cocaine-induced activity. The findings from these studies will yield a greater understanding of the neurochemical and neuroendocrine substrates regulating cocaine reward. A greater understanding of the neurochemical and neuroendocrine regulation of cocaine reward will facilitate the development of treatment for drug addiction, when hormonal factors may be especially important. PUBLIC HEALTH RELEVANCE: According to the National Survey on Drug Use and Health (NSDUH), in 2009 there were 1.6 million current cocaine users aged 12 or older, comprising 0.7 percent of the nation's population. This is a dangerous epidemic because cocaine use can produce addiction and other adverse health consequences. As evidence of the addictive consequences of cocaine use, according to the NSDUH, nearly 1.1 million Americans met the DSM-IV criteria for dependence or abuse of cocaine in 2009. Additional data also indicate that 448,481 of the total 1,449,154 visits to emergency rooms for drug abuse involved cocaine, highlighting the adverse health consequences of cocaine use. Studies presented in this proposal will examine a region of the brain that has received little attention as a potential modulator of cocaine activity. This brain region is important for the integration of endocrine stimulation into the nervous system. Since gonadal hormones modulate rewarding and gender-sensitive responses to cocaine, the preclinical findings generated upon completion of the planned experiments will help us better understand the neurochemical, neuroendocrine, and gender-relevant substrates regulating cocaine abuse. The successful completion of the proposed aims will facilitate the development of prevention and treatment strategies for addiction, especially if these strategies involve an endocrine component. Furthermore, because pharmacological and behavioral treatments affect men and women differently, then a better understanding of how hormones impact cocaine-induced brain activity, while developing future treatment, should optimize the effectiveness of those treatment strategies.

描述（由申请人提供）：大多数研究都指出中皮质上的多巴胺（DA）系统是描述可卡因的奖励性能时必要的神经生物学终点；但是，该系统并非孤立地运行，其他结构的投入可能在可卡因奖励中起重要作用。作为可卡因诱导活性的潜在调节剂的一个区域是下丘脑（MPOA）的内侧前区域。 MPOA参与了两种自然奖励行为（母亲和性行为）的调节，是性二态性的，并且与中皮质胶质系统中的区域相互作用。因此，MPOA是调节可卡因诱导活性的神经解剖基因座的逻辑候选者，但对于这种结构在药物滥用背景下的作用而言，知之甚少。在这里，我们专注于可卡因奖励的临床前动物模型，假设MPOA调节可卡因诱导的中皮质降低系统中可卡因诱导的活性，并导致奖励的行为表达，包括性别差异。拟议的研究将回答以下问题：（1）MPOA是否调节可卡因诱导的神经元和多巴胺活性？ （2）MPOA是否调制可卡因？ （3）含有性腺激素受体的MPOA中的细胞是否与中皮质胶质系统相互作用？ （4）性腺激素是否通过MPOA作用以调节可卡因诱导的神经胶质细胞降解系统中的神经元和多巴胺活性？ （5）性腺激素是否通过MPOA作用以调节可卡因奖励？使用神经解剖学，神经化学和行为测定，提出的工作将检查MPOA是否可以作为调节可卡因诱导活性的奖励途径的扩展。这些研究的发现将对调节可卡因奖励的神经化学和神经内分泌底物有更深入的了解。当激素因素可能尤为重要时，对可卡因奖励的神经化学和神经内分泌调节的了解将有助于促进药物成瘾的治疗。 公共卫生相关性：根据全国药物使用和健康调查（NSDUH），2009年，现有12岁或12岁以上的可卡因使用者占该国人口的0.7％。这是一种危险的流行病，因为可卡因的使用会产生成瘾和其他不利的健康后果。 As evidence of the addictive consequences of cocaine use, according to the NSDUH, nearly 1.1 million Americans met the DSM-IV criteria for dependence or abuse of cocaine in 2009. Additional data also indicate that 448,481 of the total 1,449,154 visits to emergency rooms for drug abuse involved cocaine, highlighting the adverse health consequences of cocaine use. 该提案中提出的研究将研究一个大脑的区域，该区域很少受到可卡因活性的潜在调节剂的关注。该大脑区域对于将内分泌刺激整合到神经系统中很重要。由于性腺激素调节对可卡因的奖励和性别敏感反应，因此计划的实验完成后产生的临床前发现将有助于我们更好地理解调节可卡因滥用的神经化学，神经内分泌和性别相关的底物。 拟议的目标的成功完成将有助于发展成瘾的预防和治疗策略，尤其是在这些策略涉及内分泌成分时。此外，由于药理和行为治疗对男人和女性的影响有所不同，因此更好地了解激素如何影响可卡因引起的大脑活动，同时开发未来的治疗，应优化这些治疗策略的有效性。