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Altered expression and functions of serotonin 5‐HT 1A and 5‐HT 1B receptors in knock‐out mice lacking the 5‐HT transporter
Author(s) -
Fabre V.,
Beaufour C.,
Evrard A.,
Rioux A.,
Hanoun N.,
Lesch K. P.,
Murphy D. L.,
Lanfumey L.,
Hamon M.,
Martres M. P.
Publication year - 2000
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2000.00126.x
Subject(s) - substantia nigra , serotonin , 5 ht receptor , medicine , endocrinology , raphe nuclei , chemistry , dorsal raphe nucleus , globus pallidus , serotonin transporter , receptor , agonist , autoreceptor , ipsapirone , neurotransmission , biology , serotonergic , dopamine , basal ganglia , central nervous system , dopaminergic
By taking up serotonin (5‐hydroxytryptamine, 5‐HT) released in the extracellular space, the 5‐HT transporter (5‐HTT) regulates central 5‐HT neurotransmission. Possible adaptive changes in 5‐HT neurotransmission in knock‐out mice that do not express the 5‐HT transporter were investigated with special focus on 5‐HT 1A and 5‐HT 1B receptors. Specific labelling with radioligands and antibodies, and competitive RT‐PCR, showed that 5‐HT 1A receptor protein 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‐HT 1B receptors because a decrease in their density was found in the substantia nigra (−30%) but not the globus pallidus of mutant mice. Intermediate changes were noted in 5‐HTT+/– mice compared with 5‐HTT+/+ and 5‐HTT–/– animals. Quantification of [ 35 S]GTP‐γ‐S binding evoked by potent 5‐HT 1 receptor agonists confirmed such changes as a decrease in this parameter was noted in the DRN (−66%) and the substantia nigra (−30%) but not other brain areas in 5‐HTT–/– vs. 5‐HTT+/+ mice. As expected from actions mediated by functional 5‐HT 1A and 5‐HT 1B autoreceptors, a decrease in brain 5‐HT turnover rate after i.p. administration of ipsapirone (a 5‐HT 1A agonist), and an increased 5‐HT outflow in the substantia nigra upon local application of GR 127935 (a 5‐HT 1B/1D antagonist) were observed in 5‐HTT+/+ mice. Such effects were not detected in 5‐HTT–/– mice, further confirming the occurrence of marked alterations of 5‐HT 1A and 5‐HT 1B autoreceptors in these animals.