Review
Serotonergic modulation of the limbic system

https://doi.org/10.1016/j.neubiorev.2005.06.007Get rights and content

Abstract

The limbic system is composed of cortical as well as subcortical structures, which are intimately interconnected. The resulting macrostructure is responsible for the generation and expression of motivational and affective states. Especially high levels of serotonin are found in limbic forebrain structures. Serotonin projections to these structures, which arise from serotonergic cell body groups in the midbrain, form a dense plexus of axonal processes. In many areas of the limbic system, serotonergic neurotransmission can best be described as paracrine or volume transmission, and thus serotonin is believed to play a neuromodulatory role in the brain. Serotonergic projections to limbic structures, arising primarily from the dorsal and median raphe nuclei, compose two distinct serotonergic systems differing in their topographic organization, electrophysiological characteristics, morphology, as well as sensitivity to neurotoxins and perhaps psychoactive or therapeutic agents. These differences may be extremely important in understanding the role of these two serotonergic systems in normal brain function and in mental illness. Central serotonergic neurons or receptors are targets for a variety of therapeutic agents used in the treatment of disorders of the limbic system.

Section snippets

Overview

The limbic system is composed of cortical as well as subcortical structures, which are intimately interconnected. The major structures of the limbic system include prefrontal cortex, cingulate cortex, entorhinal cortex, hippocampus, nucleus accumbens (ventral striatum), ventral pallidum, amygdala, and anterior hypothalamus (see Swanson and Petrovich, 1998, Kandel et al., 2000, Heimer, 2003). Connections between these structures form complex circuits. Furthermore, projections between structures

Two distinct central serotonergic systems

Serotonin-containing neuronal cell bodies are restricted to discrete groups of cells or nuclei located along the midline of the brainstem. Their axonal projections, however, innervate nearly every area of the central nervous system. Dahlström and Fuxe (1964), using the Falck–Hillarp technique of histofluorescence, observed that the majority of serotonergic soma were found in cell body groups previously designated by Taber et al. (1960) as the raphe nuclei based on cytoarchitectural criteria,

Ascending serotonergic projections to limbic structures

The dorsal periventricular path and the ventral tegmental radiations are the two main ascending serotonergic pathways from the midbrain raphe nuclei to the forebrain. Both pathways converge in the caudal hypothalamus where they join the medial forebrain bundle and axons of dopaminergic (A8, A9, A10) and noradrenergic (A6) cell body groups (Moore et al., 1978, Parent et al., 1981; see also Molliver, 1987, Vertes, 1991).

The dorsal and median raphe nuclei give rise to distinct serotonergic

Volume transmission

The action of neurotransmitters may be restricted to the synaptic cleft, specifically referred to as hard-wired neurotransmission, or may require that the neurotransmitter diffuse to remote receptor sites, referred to as diffuse, volume or paracrine transmission. Important factors determining the type of neurotransmission include the location of receptors with respect to release sites, the amount of neurotransmitter released, rate of diffusion away from the release site, and the removal or

Disorders of limbic system and treatment strategies

In humans, disorders associated with dysfunction within the limbic system include schizophrenia, major depression, and anxiety disorders. Drugs used in the treatment of these disorders modulate or alter serotonergic neurotransmission (see Jones and Blackburn, 2002).

Some considerations in the treatment of disorders of the limbic system

Serotonergic projections from the dorsal and median raphe differ in the topographical organization and density of their respective innervation of forebrain structures. With regard to the treatment of affective disorders, i.e. major depression and anxiety disorders, it is an intriguing possibility that these two distinct serotonergic systems are differentially modulated by drugs that block serotonin reuptake (e.g. tricyclic antidepressants and selective serotonin reuptake inhibitors). Indeed,

Acknowledgements

This work was supported by US PHS grants MH 52369 and funds from the National Association for Research on Schizophrenia and Depression (NARSAD).

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