Altered expression and functions of serotonin 5‐HT_1A and 5‐HT_1B receptors in knock‐out mice lacking the 5‐HT transporter

Abstract

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-HT1A and 5-HT1B receptors. Specific labelling with radioligands and antibodies, and competitive RT-PCR, showed that 5-HT1A 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-HT1B 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 [35S]GTP-gamma-S binding evoked by potent 5-HT1 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-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 increased 5-HT outflow in the substantia nigra upon local application of GR 127935 (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 marked alterations of 5-HT1A and 5-HT1B autoreceptors in these animals.

5-HT1A/1B Receptor-Mediated Effects of the Selective Serotonin Reuptake Inhibitor, Citalopram, on Sleep: Studies in 5-HT1A and 5-HT1B Knockout Mice

“…The PS inhibition induced by the SSRI citalopram is most probably the consequence of the enhancement of extracellular 5-HT levels resulting from blockade of the amine reuptake (Fuller, 1994;Malagié et al, 1995;Fabre et al, 2000). Among the receptors at which 5-HT in excess could act to induce PS inhibition, the 5-HT 1A and 5-HT 1B types appeared as the most relevant candidates (Dzoljic et al, 1992;Tissier et al, 1993;Bjorvatn and Ursin, 1994;Monti et al, 1995;Bjorvatn et al, 1997;Boutrel et al, 1999Boutrel et al, , 2002.…”

Homeostatic Regulation of Sleep in a Genetic Model of Depression in the Mouse: Effects of Muscarinic and 5-HT1A Receptor Activation

“…This apparent discrepancy is due to the fact that the sleep response is mediated by post-synaptic 5-HT 1A receptors (Tissier et al, 1993), possibly at pontine level (Horner et al, 1997), whereas the hypothermic response is mediated by pre-synaptic (auto-) receptors (Goodwin et al, 1985). Indeed, the latter receptors are functionally hypersensitive in H mice (El Yacoubi et al, 2003), whereas the post-synaptic ones are unchanged, as observed under various experimental conditions (Fabre et al, 2000, Hensler, 2003.…”

Interaction of nitric oxide and serotonin in aggressive behavior

“…The absence of the 5-HTT gene (5-HTT Ϫ/Ϫ ) in mice perturbs 5-HT neurotransmission demonstrated by increased basal levels of extracellular 5-HT (Mathews et al, 2000;Daws et al, 2001) and several compensatory alterations in 5-HT homeostasis (Bengel et al, 1998;Li et al, 1999;Rioux et al, 1999;Fabre et al, 2000;Gobbi et al, 2001;La Cour et al, 2001). As expected, male 5-HTT Ϫ/Ϫ mice are less aggressive than WT animals (Holmes et al, 2002).…”