Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter

By taking up serotonin (5-hydroxytryptamine, 5-HT) released in the extracel lular space, the 5-HT transporter (5-HTT) regulates central 5-HT neurotrans mission. Possible adaptive changes in 5-HT neurotransmission in knock-out m ice that do not express the 5-HT transporter were investigated with special focus on 5-HT1A and 5-HT1B receptors. Specific labelling with radioligands and antibodies, and competitive RT-PCR, showed that 5-HT1A receptor protei n and mRNA levels were significantly decreased in the dorsal raphe nucleus (DRN), increased in the hippocampus and unchanged in other forebrain areas of 5-HTT-/- vs. 5-HTT+/+ mice. Such regional differences also concerned 5-H T1B receptors because a decrease in their density was found in the substant ia nigra (-30%) but not the globus pallidus of mutant mice. Intermediate ch anges were noted in 5-HTT+/- mice compared with 5-HTT+/+ and 5-HTT-/- anima ls. Quantification of [S-35]GTP-gamma-S binding evoked by potent 5-HT1 rece ptor agonists confirmed such changes as a decrease in this parameter was no ted in the DRN (-66%) and the substantia nigra (-30%) but not other brain a reas in 5-HTT-/- vs. 5-HTT+/+ mice. As expected from actions mediated by fu nctional 5-HT1A and 5-HT1B autoreceptors, a decrease in brain 5-HT turnover rate after i.p. administration of ipsapirone (a 5-HT1A agonist), and an in creased 5-HT outflow in the substantia nigra upon local application of GR 1 27935 (a 5-HT1B/1D antagonist) were observed in 5-HTT+/+ mice. Such effects were not detected in 5-HTT-/- mice, further confirming the occurrence of m arked alterations of 5-HT1A and 5-HT1B autoreceptors in these animals.