Modulation of Dopaminergic VTA Neurons by Urotensin II

尾加压素 II 对多巴胺能 VTA 神经元的调节

• 批准号: 8515980
• 负责人: Stewart Donaldson Clark
• 金额: $ 23.9万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515980
• 关键词: Award; Behavior; Behavioral Paradigm; Binding; Biological Assay; Brain Stem; Cell Nucleus; Complex; Development; Diphtheria Toxin; Dopamine; Drug Addiction; Drug Targeting; Electron Microscopy; Fusion Toxin; Future; Genes; Genetic Predisposition to Disease; Goals; Heterogeneity; In Vitro; Instruction; Investigation; Maintenance; Microdialysis; Molecular; Motivation; Neurobiology; Neuromodulator; Neuronal Plasticity; Neurons; Neuropeptides; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Postdoctoral Fellow; Production; Psychotropic Drugs; Quality Control; Recombinants; Regulation; Role; Self Administration; Side; Structure; Synapses; System; Testing; Tissues; Toxin; Ventral Tegmental Area; Work; addiction; dopaminergic neuron; in vivo; motivational processes; neuronal circuitry; novel; preference; prepulse inhibition; radioligand; receptor; reinforced behavior; reward processing; urotensin II

The mesolimbic pathway through the release of dopamine from neurons in the ventral tegmental area (VTA), which project to the nucleus accumbens (NAc), is thought to have a role in motivation and reward processes. Some addictive drugs produce their potent effects on behavior by enhancing mesolimbic dopamine activity. Release of dopamine from VTA neurons is controlled by various factors and neuronal structures. One pathway providing regulatory input to the VTA originates in the mesopontine nuclei of the brainstem. We have previously shown that the mesopontine-VTA-NAc pathway is modulated by the novel neuropeptide urotensin II (Uil). To facilitate our studies we have developed and validated a fusion of diphtheria toxin with UN (Dtx-Uli). This toxin is able to selectively ablate Ull-R expressing neurons of the mesopontine without damage to surrounding tissue. Through the combination ofthis toxin with microdialysis and behavioral paradigms (self-administration and conditioned place preference), we will establish whether Uil can modulate reinforced behaviors. In addition, to better understand the function ofthe mesopontine nuclei, the Dtx-Uli will be used to ablate neurons of this region. Subsequently, different aspects of proposed mesopontine function will be tested ( ex. prepulse inhibition, conditioned place preference). Drug addiction is a multifactorial condition. This heterogeneity is partly due to genetic predisposition. Any gene that is expressed in the neuronal circuitry known to modulate the acquisition and maintenance of addiction could impact the development of an addiction, although that gene may not be the direct target of the drug. Uil is an emerging neuromodulator which may have implications in addiction and the development of addiction. Furthermore, in other work UN has been shown to produce cellular remolding, which may point to a role in neuroplasticity. Therefore, future studies will include the investigation ofthe role of Ull-R in molecular neurobiological changes and the development of addiction.

腹侧对腹侧段区域的多巴胺的中唇途径 （VTA）投射到伏隔核（NAC）的（NAC），被认为在动机和奖励中起作用 过程。一些令人上瘾的药物通过增强中唇而对行为产生有效的影响 多巴胺活性。从VTA神经元中释放多巴胺由各种因素和神经元控制 结构。为VTA提供调节输入的一种途径源自中桥核的核 脑干。我们先前已经表明，中桥 - VTA-NAC途径是由小说调节的 神经肽尿素II（UIL）。 为了促进我们的研究，我们已经开发并验证了白喉毒素与联合国（DTX-ULI）的融合。这 毒素能够选择性地烧蚀室桥桥的神经元，而不会损害 周围的组织。通过这种毒素与微透析和行为范例的结合 （自我管理和有条件的地点偏好），我们将确定UIL是否可以调节 加强行为。另外，为了更好地了解中桥核的功能，DTX-ULI将 被用来消融该区域的神经元。随后，提出的中桥函数的不同方面 将进行测试（例如，预脉冲抑制，条件的位置偏好）。 吸毒成瘾是多因素的条件。这种异质性部分是由于遗传倾向。任何 在神经元电路中表达的基因已知可调节的采集和维护 成瘾可能会影响成瘾的发展，尽管该基因可能不是 药物。 UIL是一种新兴的神经调节剂，可能对成瘾和发展具有影响 成瘾。此外，在其他工作中，联合国已证明会产生细胞归还，这可能点 在神经塑性中发挥作用。因此，未来的研究将包括对ULL-R在中的作用的研究 分子神经生物学的变化和成瘾的发展。