PhD Program in Behavioral Neuroscience, Department of Psychology, University of Rome "Sapienza".
IRCSS Fondazione Santa Lucia, Department of Experimental Neurosciences.
Behav Pharmacol. 2021 Aug 1;32(5):392-403. doi: 10.1097/FBP.0000000000000629.
Individual variability in the response to pharmacological therapies is a major problem in the treatment of psychiatric disorders. Comparative studies of phenotypes expressed by mice of the C57BL/6J (C57) and DBA/2J (DBA) inbred strains can help identify neurobiological determinants of this variability at preclinical levels. We have recently demonstrated that whereas young adult mice of both strains develop sign-tracking in a Pavlovian Conditioned Approach (PCA), a trait associated with dysfunctional behavior in rat models, in full adult C57 mice acquisition of this phenotype is inhibited by pre-frontal cortical (PFC) serotonin (5HT) transmission. These findings suggest a different role of 5HT transmission on sign-tracking development in mice of the two genotypes. In the present experiments, we tested the effects of the 5-HT synthesis booster 5-hydroxytryptophan (5-HTP) and of the selective 5HT reuptake inhibitor (SSRI) fluoxetine on the development and expression of sign-tracking in young adult mice from both inbred strains. In mice of the C57 strain, administration of 5-HTP before each training session blocked the training-induced shift to positive PCA scores which indicates the development of sign-tracking, whereas the same treatment was ineffective in mice of DBA strain. On the other hand, a single administration of fluoxetine was ineffective in unhandled saline- and 5-HTP-treated C57 mice, whereas it enhanced the expression of positive PCA scores by mice of DBA strain treated with 5-HTP during training. These findings confirm the strain-specific inhibitory role of PFC 5-HT transmission on sign-tracking development by mice of the C57 strain and support the hypothesis that different genotype-specific neurobiological substrates of dysfunctional phenotypes contribute to variable effects of pharmacotherapies.
个体对药物治疗的反应存在差异，这是精神疾病治疗中的一个主要问题。对 C57BL/6J（C57）和 DBA/2J（DBA）近交系小鼠表型的比较研究有助于在临床前水平确定这种变异性的神经生物学决定因素。我们最近证明，尽管两种品系的年轻成年小鼠都在巴甫洛夫条件性趋近（PCA）中表现出信号跟踪，这是大鼠模型中功能障碍行为的一个特征，但在完全成年的 C57 小鼠中，这种表型的获得受到前额皮质（PFC）血清素（5HT）传递的抑制。这些发现表明 5HT 传递在两种基因型小鼠的信号跟踪发展中具有不同的作用。在本实验中，我们测试了 5-羟色氨酸（5-HTP）这种 5-HT 合成促进剂和选择性 5-HT 再摄取抑制剂（SSRI）氟西汀对两种近交系年轻成年小鼠信号跟踪发展和表达的影响。在 C57 品系的小鼠中，在每次训练前给予 5-HTP 可阻断训练引起的正向 PCA 评分的转变，这表明信号跟踪的发展，而在 DBA 品系的小鼠中，相同的处理是无效的。另一方面，单次给予氟西汀对未处理的生理盐水和 5-HTP 处理的 C57 小鼠无效，但它增强了 5-HTP 处理的 DBA 品系小鼠在训练期间正向 PCA 评分的表达。这些发现证实了 PFC 5-HT 传递对 C57 品系小鼠信号跟踪发展的特定抑制作用，并支持了这样一种假设，即不同基因型特异性的功能障碍表型的神经生物学基础导致药物治疗的可变效果。
