A Role for the Preoptic Area in Modulating Cocaine Reward

描述(由申请人提供)：大多数研究指出，在描述可卡因的奖赏特性时，中皮质边缘多巴胺(DA)系统是必要的神经生物学终点；然而，该系统不是孤立运行的，来自其他结构的输入可能在可卡因奖赏中发挥重要作用。作为可卡因诱导活动的潜在调节器，下丘脑内侧视前区(MPOA)几乎没有受到关注。MPOA参与调节两种自然奖赏行为(母性行为和性行为)，是性二态的，并与中皮质边缘系统的区域相互作用。因此，MPOA是调节可卡因诱导活动的神经解剖学位点的合理候选者，但令人惊讶的是，人们对这一结构在药物滥用背景下的作用知之甚少。在这里，我们关注可卡因奖赏的临床前动物模型，假设MPOA调节可卡因诱导的中皮质边缘系统的活动，并由此产生奖赏的行为表达，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中皮质边缘系统的神经元和多巴胺活动？(2)MPOA是否调节可卡因奖励？(3)含有性激素受体的MPOA中的细胞是否与中皮质边缘系统相互作用？(4)性腺激素是否通过MPOA作用于调节可卡因诱导的中皮质边缘系统的神经元和多巴胺活动？(5)性腺激素是否通过MPOA作用于调节可卡因奖励？利用神经解剖学、神经化学和行为分析，这项拟议的工作将检验MPOA是否可以作为调节可卡因诱导活动的奖励途径的延伸。这些研究的发现将使人们更好地理解调节可卡因奖励的神经化学和神经内分泌底物。更好地了解可卡因奖赏的神经化学和神经内分泌调节将有助于药物成瘾治疗的发展，因为激素因素可能特别重要。 公共卫生相关性：根据全国毒品使用与健康调查(NSDUH)，2009年有160万12岁及以上的当前可卡因使用者，占全国人口的0.7%。这是一种危险的流行病，因为使用可卡因会导致上瘾和其他有害的健康后果。根据NSDUH的数据，作为可卡因使用令人上瘾的后果的证据，2009年有近110万美国人符合DSM-IV可卡因依赖或滥用标准。其他数据还表明，在因滥用药物而到急诊室就诊的1 449 154人次中，有448 481人次涉及可卡因，这突出表明了使用可卡因对健康造成的不良后果。这项提案中提出的研究将检查大脑中一个几乎没有受到关注的区域，它是可卡因活动的潜在调节器。这一大脑区域对于内分泌刺激与神经系统的整合非常重要。由于性腺激素调节对可卡因的奖赏和性别敏感反应，计划中的实验完成后产生的临床前发现将有助于我们更好地了解调控可卡因滥用的神经化学、神经内分泌和性别相关底物。成功完成拟议的目标将有助于制定成瘾预防和治疗战略，特别是如果这些战略涉及内分泌部分的话。此外，由于药物和行为治疗对男性和女性的影响不同，因此，在开发未来的治疗方法时，更好地了解激素如何影响可卡因诱导的大脑活动，应该会优化这些治疗策略的有效性。

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.