Trends in Neurosciences
Volume 23, Issue 10, 1 October 2000, Pages 459-465
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Control of dorsal raphé 5-HT function by multiple 5-HT1 autoreceptors: parallel purposes or pointless plurality?

https://doi.org/10.1016/S0166-2236(00)01631-3Get rights and content

Abstract

The serotonergic cells of the dorsal raphé nucleus innervate much of the forebrain and are thought to be involved in the mechanism of action of antidepressants. Dysfunction of these cells might be involved in the neural mechanisms underlying depression and suicide. The traffic in pathways emanating from the dorsal raphé nucleus is controlled by 5-HT1 autoreceptors. Until recently it was thought that the autoreceptors in the dorsal raphé nucleus were solely of the 5-HT1A subtype. In this article, we discuss evidence that the situation is more complex and that multiple 5-HT1 subtypes govern different aspects of 5-HT function in the dorsal raphé nucleus presenting new therapeutic opportunities.

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.

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