These findings indicate that ST phenotype can be the expression of a transitory late developmental stage and that genetic factors determine persistence of this phenotype in adulthood. These findings also support a role of 5-HT transmission in PFC in constraining development of ST phenotype.

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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.