Trends in Neurosciences
Volume 22, Issue 9, 1 September 1999, Pages 377-382
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Paracrine neurotransmission in the CNS: involvement of 5-HT

https://doi.org/10.1016/S0166-2236(99)01410-1Get rights and content

Abstract

While GABA and glutamate have an established synaptic function in the CNS, recent evidence suggests 5-HT neurotransmission is predominantly paracrine. As the amino-acid neurotransmitters interact with receptors that produce effects rapidly, electrophysiological approaches can be used to assess the time delay between transmitter release and the postsynaptic response directly. However, this approach cannot be used for studies of 5-HT-mediated neurotransmission, because the majority of its receptors react more slowly, so anatomical and voltammetrical approaches have been used to provide insight into 5-HT-mediated events. These studies have revealed that extrasynaptic receptors and transporters for 5-HT exist, and that 5-HT escapes readily from the synaptic cleft. Attenuation of 5-HT binding by 5-HT-receptor antagonists and 5-HT-uptake inhibitors does not affect the synaptic efflux elicited by transient stimuli, although the effects of such drugs are apparent at later time points. Once it is extrasynaptic, 5-HT has a concentration that is similar to those estimated to be optimal for receptor and transporter activation, and it can diffuse a few micrometers until removed by its transporter. These properties of 5-HT raise the possibility that it can act on receptors that are distant from its release site and function as a paracrine transmitter.

Section snippets

GABAergic and glutamatergic neurotransmission: examples of synaptic transmission

The most direct way to evaluate synaptic neurotransmission is to measure the time course between synaptic release and the response at a postsynaptic neuron. The binding of neurotransmitters whose receptors are ligand-gated ion channels, such as glutamate9 and GABA (Ref. 10), results in an almost immediate postsynaptic response. Thus, diffusion of released neurotransmitters to receptor sites and the subsequent binding of these neurotransmitters are the rate-limiting factors for the postsynaptic

Architecture of serotonergic nerve terminals

Because 5-HT exerts many of its actions via G-protein coupled receptors, the postsynaptic responses that follow receptor binding are slower than those elicited by the ligand-gated ion channels, and direct electrophysiological approaches to distinguish synaptic and paracrine neurotransmission cannot be used. However, the synaptic morphology and the location and quantity of release sites, receptors and transporters have been characterized in several regions of the brain. Furthermore,

Voltammetrical studies

Early work with carbon-fiber microelectrodes showed that 5-HT could be detected following release elicited by electrical stimulation34. Improvements in the technique led to real-time measurements of its concentration changes35. The sequence of events during detection is shown in Fig. 2. Given that the tip diameter of the carbon-fiber electrode is 10–15 μm, these measurements are of extracellular, rather than synaptic, concentrations. With Nafion-coated electrodes, diffusion through the coating

Quantitative evaluation of elicited release

In order to evaluate the likelihood that 5-HT leaves the synaptic cleft, it is preferable to use a single electrical impulse. Efflux during stimulus trains can be enhanced because of the occupancy of uptake sites and receptor binding sites within the synaptic cleft by previously released neurotransmitter. Furthermore, short trains ensure that release is not modulated by autoreceptor activation38.

In both the DR and SNr, the 5-HT concentration elicited by single stimulation pulses was compared

Paracrine transmission in the brain

As reviewed in this article, 5-HT is emerging as a prominent paracrine neurotransmitter in the brain regions investigated. Surprisingly, paracrine neurotransmission is found in regions where terminals are junctional (SNr) or predominantly nonjunctional (DR). Although the spatial dimensions of the voltammetrical probe preclude direct measurements of synaptic concentrations, voltammetrical measurements nonetheless provide predictive results and conclusions concerning paracrine neurotransmission.

Acknowledgements

The authors’ research was supported by the National Institute of Health (NS 15841).

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