Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents.
Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents.
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DOI：
10.1371/journal.pone.0146966
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Leslie FM
中科院分区：
文献类型：
--
作者：
Dwyer JB;Leslie FM
青春期是一个发育时期，其特点是对非法药物使用的脆弱性增加，并出现神经精神障碍。这些临床现象可能共享共同的神经生物学底物，因为在这一时期中皮质边缘多巴胺系统活跃成熟。虽然先前的研究考察了多巴胺受体结合的年龄相关性变化，但功能分析较少。因此，本研究的目的是确定D1样和D2样激活的功能后果是否与年龄相关。青春期和成年大鼠分别给予直接的D1和D2激动剂，单独和联合使用。测量大鼠的运动和刻板行为，并收集脑组织，分析即刻早期基因(IEGs)、CFos和Arc的mRNA表达。青少年表现出增强的D2样受体对运动和重复行为的控制，这在成年后过渡到主导的D1样机制。当小剂量激动剂联合使用时，成人对d1/d2组合表现出超加性行为反应，而青少年则没有，这可能表明在d1/d2协同作用方面存在年龄差异。D_1/D_2刺激的IEG在终纹床核(BNST)的表达尤为显著。鉴于BNST作为皮质纹状体、海马和应激相关回路的集成者的功能，以及神经网络动力学在产生行为中的重要性，我们对区域IEG表达进行了探索性的功能网络分析。这一数据驱动的分析显示了与在人类中描述的相似的发展轨迹，并表明多巴胺能药物改变前脑协调基因表达的年龄依赖性。在青少年中，D1/D2应激核重新聚集到功能网络与低行为输出有关。网络分析提供了一种评估药理作用的新工具，并突出了功能神经回路的关键发育变化。青少年不成熟的d1/d2相互作用可能是他们对滥用药物和易受精神病理影响的独特反应的基础。这些数据突显了青春期特定年龄药物治疗设计和临床应用的必要性。
Adolescence is a developmental period characterized by heightened vulnerability to illicit drug use and the onset of neuropsychiatric disorders. These clinical phenomena likely share common neurobiological substrates, as mesocorticolimbic dopamine systems actively mature during this period. Whereas prior studies have examined age-dependent changes in dopamine receptor binding, there have been fewer functional analyses. The aim of the present study was therefore to determine whether the functional consequences of D1 and D2-like activation are age-dependent. Adolescent and adult rats were given direct D1 and D2 agonists, alone and in combination. Locomotor and stereotypic behaviors were measured, and brains were collected for analysis of mRNA expression for the immediate early genes (IEGs), cfos and arc. Adolescents showed enhanced D2-like receptor control of locomotor and repetitive behaviors, which transitioned to dominant D1-like mechanisms in adulthood. When low doses of agonists were co-administered, adults showed supra-additive behavioral responses to D1/D2 combinations, whereas adolescents did not, which may suggest age differences in D1/D2 synergy. D1/D2-stimulated IEG expression was particularly prominent in the bed nucleus of the stria terminalis (BNST). Given the BNST’s function as an integrator of corticostriatal, hippocampal, and stress-related circuitry, and the importance of neural network dynamics in producing behavior, an exploratory functional network analysis of regional IEG expression was performed. This data-driven analysis demonstrated similar developmental trajectories as those described in humans and suggested that dopaminergic drugs alter forebrain coordinated gene expression age dependently. D1/D2 recruitment of stress nuclei into functional networks was associated with low behavioral output in adolescents. Network analysis presents a novel tool to assess pharmacological action, and highlights critical developmental changes in functional neural circuitry. Immature D1/D2 interactions in adolescents may underlie their unique responses to drugs of abuse and vulnerability to psychopathology. These data highlight the need for age-specific pharmacotherapy design and clinical application in adolescence.