Study on the pharmacological basis for the effect of psychological stress in the early life stage on response to psychotropic drugs

本研究旨在阐明生命早期心理应激对精神药物药理反应的影响机制，以此作为涉及情绪的神经网络发展的后遗症。首先，我们利用活体微透析技术，研究了非典型抗精神病药物诱导大鼠前额叶皮质多巴胺释放的药理学基础。结果提示，根据与突触前多巴胺D2自身受体结合方式的不同，不同类型的非典型抗精神病药物对腹侧被盖区投射到前额叶皮质的多巴胺神经元的活动可能有不同的影响。此外，非典型抗精神病药物局部应用于内侧前额叶皮质的实验结果表明，在前额叶皮质的局部环路中，弱的D2拮抗剂和强的5-羟色胺(5-羟色胺)1A受体激动剂之间的相互作用可能是…。更多归功于氯氮平和阿立哌唑增加前额叶多巴胺释放的能力。因此，这些单胺受体亚型在发育期前额叶皮质中的表达和成熟可能参与了临床对精神药物的反应。第二，生命早期的心理应激增加了促肾上腺皮质激素释放因子(CRF)的表达，从而对神经元网络的发育产生持久的影响。因此，我们研究了CRF1受体选择性拮抗剂对成年和幼年大鼠前额叶皮质多巴胺释放的影响。结果发现，CRF1拮抗剂对应激诱导的多巴胺释放的调节能力在成年(6~8周龄)大鼠和幼年(3周龄)大鼠之间存在显著差异。这些结果表明，CRF1受体在多巴胺能应激反应中的生理作用在发育阶段可能会发生变化。由于个体对压力源的反应差异很大，还需要进一步的研究。较少

This study aims to elucidate the mechanism for the influence of psychological stress in the early life stage on pharmacological response to psychotropic drugs as a sequel of the enduring changes in development of the neuronal network involving emotion.Fist, we examined the pharmacological basis for the ability of atypical antipsychotic drugs to induce dopamine release in rat prefrontal cortex, using in vivo microdialysis. The results suggest that, depending on the manner of binding to presynaptic dopamine-D2 autoreceptors, different types of atypical antipsychotic drugs may have distinct effects on the activity of dopamine neurons projecting from the ventral tegmental area to the prefrontal cortex. Moreover, the results from the experiment of local application with atypical antipsychotic drugs into the medial prefrontal cortex suggest that the interaction between weak D2 antagonism and potent serotonin (5-HT) 1A receptor agonism within the local circuitry of the prefrontal cortex may c … More ontribute to the ability of clozapine and aripiprazole to increase prefrontal dopamine release. Therefore, expression and maturation of these monoamine receptor subtypes in the prefrontal cortex during the developmental stage may be involved in the clinical response to psychotropic drugs.Second, psychological stress in the early life stage has been thought to increase expression of corticotrophin-releasing factor (CRF), resulting in the enduring effect on development of the neuronal network. We therefore investigated the effect of the selective antagonist for CRF1 receptors on dopamine release in the prefrontal cortex of adult and young rats. As the results, a significant difference in the ability of CRF1 antagonist to modulate stress-induced dopamine release was found between adult (age of six to eight weeks) and young (age of three weeks) rats. These results suggest that the physiological role of CRF1 receptors in the dopaminergic response to stressors may change during the developmental stage. Further studies are needed because individual responses to stressors differed widely. Less