Trends in Neurosciences
ViewpointControl of dorsal raphé 5-HT function by multiple 5-HT1 autoreceptors: parallel purposes or pointless plurality?
Section snippets
DRN 5-HT cell firing
Serotonergic cell firing in the DRN is primarily under 5-HT1A control. For example, Sprouse and Aghajanian10 showed that 5-HT1A agonists (e.g. ipsapirone) but not 5-HT1B agonists (e.g. TFMPP) inhibited DRN firing in anaesthetized rats. Much of this control is exerted locally: ipsapirone (100 nm) decreased cell firing in rat DRN slices, an effect that is blockable by spiperone (100 nm)11. Furthermore, 5-HT (30 μm), 5-CT (10 nm) and the selective 5-HT1A receptor agonist 8-OH-DPAT (30 nm) have
DRN 5-HT release
In addition to controlling cell firing, somatodendritic 5-HT1A autoreceptors also regulate DRN 5-HT release. It is well established that 5-HT1A agonists decrease basal DRN 5-HT release in vivo21, 22 and stimulated DRN 5-HT release in vitro23, 24. Furthermore, considerable evidence now suggests that other 5-HT1 subtypes also negatively modulate intra-raphé 5-HT release (although there is a clear disparity between some in vivo and in vitro studies).
Early in vitro data, using voltammetry in rat
Location of the receptors
The data above show that multiple 5-HT1 subtypes exist in the DRN and modulate 5-HT function therein. Furthermore, it is apparent that 5-HT release and cell firing might be independently governed. Whereas cell firing appears mainly, if not wholly, under 5-HT1A receptor control, 5-HT release is influenced by 5-HT1A, 5-HT1D and, we believe, 5-HT1B receptors. Accepting the argument that these subtypes are all found in the DRN, it is important to know their location(s) because this has obvious
Synthesis of possibilities
Why is there a need for multiple 5-HT1 subtypes and why does it matter? When referring to multiple 5-HT1 subtypes, Mendez et al.51 stated that ‘…comparison of results across studies suggests that the receptors may be functionally equivalent, bringing into question the significance of expression of multiple subtypes in brain’.
5-HT1A, 5-HT1B and 5-HT1D receptors show similar affinities for their natural ligand, 5-HT. Furthermore, although there are demonstrable differences in the coupling of 5-HT
Concluding remarks
In summary, we believe that 5-HT efflux in the DRN is governed by 5-HT1A, 5-HT1B and 5-HT1D receptors, each differentially located and with subtly different, if parallel, roles. Bearing in mind the importance of central serotonergic neurotransmission in the action of antidepressants, these receptors and their interactions might constitute important drug targets. Box 2 summarizes the involvement of multiple DRN 5-HT1 subtypes in antidepressant action.
Obviously the DRN is only one component of
Acknowledgements
Most of the authors’ research cited above was conducted with financial support from the Royal London Hospital Special Trustees, SmithKline Beecham and the Nuffield Foundation. The authors thank Catarina Owesson for the section on which Fig. 1 is based.
References (53)
Molecular cloning and characterization of a rat brain cDNA encoding a 5-hydroxytryptamine1B receptor
EMBO J.
(1991)- et al.
Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors
Brain Res.
(1985) Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat
Br. J. Pharmacol.
(1999)Effects of the 5-HT1D receptor antagonist GR127935 on extracellular levels of 5-HT in the guinea-pig frontal cortex as measured by microdialysis
Neuropharmacology
(1996)5-HT1A receptor agonist effects of BMY-14802 on serotonin release in dorsal raphe and hippocampus
Eur. J. Pharmacol.
(1996)- et al.
5-HT1D as well as 5-HT1A autoreceptors modulate 5-HT release in the guinea-pig dorsal raphe nucleus
Neuropharmacology
(1994) - et al.
Evidence that 5-hydroxytryptamine release in rat dorsal raphe nucleus is controlled by 5-HT1A, 5-HT1B and 5-HT1D autoreceptors
Br. J. Pharmacol.
(1995) Regulation of [3H]5-HT release in raphe, frontal cortex and hippocampus of 5-HT1B knock-out mice
NeuroReport
(1995)- et al.
5-HT autoreceptors in the regulation of 5-HT release from guinea pig raphe nucleus and hypothalamus
Neuropharmacology
(1997) Biochemical and behavioural studies of the 5-HT1B receptor agonist, CP-94253
Drug Dev. Res.
(1992)
Co-localization of 5-HT1B and 5-HT1D receptor mRNA in serotonergic cell bodies in guinea pig dorsal raphe nucleus: a double labeling in situ hybridization histochemistry study
Neurosci. Lett.
Serotonin-containing structures in the nucleus raphe dorsalis of the cat: an ultrastructural analysis of dendrites, presynaptic dendrites, and axon terminals
J. Comp. Neurol.
Ultrastructural localization of 5-hydroxytryptamine1A receptors in the rat brain
J. Neurosci. Res.
Production and characterization of an anti-serotonin 1A receptor antibody which detects functional 5-HT1A binding sites
Mol. Brain Res.
Effect of the selective lesion of serotoninergic neurons on the regional distribution of 5-HT1A receptor mRNA in the rat brain
Mol. Brain Res.
In situ hybridization evidence for the synthesis of 5-HT1B receptor in serotoninergic neurons of anterior raphe nuclei in the rat brain
Synapse
Cellular and subcellular localization of 5-hydroxytryptamine1B receptors in the rat central nervous system: immunocytochemical, autoradiographic and lesion studies
Neuroscience
Presynaptic inhibition by 5-HT1B receptors of glutamatergic synaptic inputs onto serotonergic caudal raphe neurones in rat
J. Physiol.
Serotonin 5-HT1B and 5-HT1D receptors form homodimers when expressed alone and heterodimers when co-expressed
FEBS Lett.
Electrophysiological evidence for a functional differentiation between subtypes of the 5-HT1 receptor
Eur. J. Pharmacol.
A review of central 5-HT receptors and their function
Neuropharmacology
Anatomy of the serotonergic system
Ann. New York Acad. Sci.
Alignment of receptor nomenclature with the human genome: classification of 5-HT1B and 5-HT1D subtypes
Trends Pharmacol. Sci.
Distinct 5-HT1B and 5-HT1D serotonin receptors in rat: structural and pharmacological comparison of the two cloned receptors
Mol. Cell. Neurosci.
Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats
J. Neurosci.
Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain
Naunyn-Schmiedeberg’s Arch. Pharmacol.
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