Elsevier

Neuroscience

Volume 166, Issue 4, 14 April 2010, Pages 1023-1035
Neuroscience

Behavioural Neuroscience
Review
Reward and the serotonergic system

https://doi.org/10.1016/j.neuroscience.2010.01.036Get rights and content

Abstract

Anhedonia, as a failure to experience rewarding stimuli, is a key characteristic of many psychiatric disorders including depression and schizophrenia. Investigations on the neurobiological correlates of reward and hedonia/anhedonia have been a growing subject of research demonstrating several neuromodulators to mediate different aspects of reward processing. Whereas the majority of research on reward mainly focused on the dopamine and opioid systems, a serotonergic mechanism has been neglected. However, recent promising results strengthen the pivotal role of serotonin in reward processing. Evidence includes electrophysical and pharmacological as well as genetic and imaging studies. Primate research using single-unit recording of neurons within the dorsal raphe nucleus argues for a serotonergic mediation of reward value, whereas studies using intracranial self-stimulation point to an important contribution of serotonin in modulating motivational aspects of rewarding brain stimulation. Pharmacological studies using agonists and antagonists of serotonergic receptor subtypes and approaches investigating an increase or decrease of the extracellular level of serotonin offer strong evidence for a serotonergic mediation, ranging from aversion to pleasure. This review provides an argument for serotonin as a fundamental mediator of emotional, motivational and cognitive aspects of reward representation, which makes it possibly as important as dopamine for reward processing.

Section snippets

Cortical and subcortical representations of reward processing

It is important to keep in mind that the term reward comprises multiple components that encompass hedonia, motivation and learning (Salamone et al., 2007, Berridge and Kringelbach, 2008). Major “hedonic hotspots” have been located in the nucleus accumbens shell (NAcc), the ventral pallidum and the parabrachial nucleus of the pons (Berridge and Kringelbach, 2008). Subsets of neurons also encoding motivation have been found within the NAcc and ventral pallidum, and also in the substancia nigra,

Serotonergic projections and reward-related areas

A prerequisite for the hypothesis of a serotonergic account in reward processing is to show that reward related areas are strongly interconnected with serotonergic neurons. The serotonergic system is composed of neurons, whose cell bodies form several nuclei located at the midline of the mesencephalon and medullary brainstem. Among them, two superior nuclei, the dorsal and median raphe nucleus (DRN and MRN), project to a range of limbic and forebrain regions (for reviews, see Lechin et al., 2006

Serotonin transporter and receptor distribution within reward-related areas

Another prerequisite for the above mentioned hypothesis is to show that reward processing areas show distinct densities of 5-HT receptor subtypes, which differentially mediate the effects of serotonergic transmission. Whereas density of the main inhibitory receptor subtype (5-HT1A) is high in the raphe nuclei, the OFC and ACC, it is low in the VTA, striatum and amygdala (Hall et al., 1997). Density of the main excitatory receptor subtype (5-HT2A) is high also in OFC and ACC, but low in the

Direct associations between serotonergic neurotransmission and reward processing

Strong support for the hypothesis of this review comes from studies showing either neuronal firing of serotonergic neurons or local release of serotonin to be closely correlated with rewarding experiences or activities. Even more support is received by studies showing rewarding behaviour to be altered due to an experimentally induced alteration of local serotonin release or 5-HT neuron firing.

Effects of changing extracellular serotonin level in the brain

There are numerous studies using rodents, non-human primates and humans that found reward behavior to be altered due to an increase or decrease in serotonin function (see supplementary information). Briefly, studies investigating increased serotonin level using SSRIs in various reward paradigms obtained both reward decreasing (e.g., Hoebel et al., 1989) as well as reward increasing effects (Subhan et al., 2000). Whereas the former effect was mainly interpreted as an inhibitory influence of

Neuroimaging

Although only correlative, neuroimaging studies give the unique opportunity to investigate a potential role of serotonin in reward in human subjects. Especially multimodal neuroimaging studies combining positron emission tomography (PET) and fMRI can demonstrate a potential serotonergic influence on neural activation underlying reward processing.

Genetic evidence

For a comprehensive summary of the genetic account on reward processing, the reader is referred to the supplementary section. There is evidence from rodents (e.g., Bearer et al., 2009), non-human primates (e.g., Watson et al., 2009) and humans (e.g., Frodl et al., 2008, Schmitz et al., 2008) that indicates alterations of both anatomical reward circuits and reward-related behavior associated with gene knockout and polymorphisms of serotonin related genes. Such genetic studies reveal a

Drug reward and the serotonergic system

There is a great corpus of studies showing that serotonin systems have major relevance for reward-related behaviors in the context of drug abuse (see Higgins and Fletcher, 2003, Muller et al., 2007 for review). Although the rewarding effects of drugs are frequently investigated in order to reach a broader understanding of the neurochemical basis of reward in general, in depth analysis of the various aspects of serotonergic function in drug reward would go beyond the scope of this review.

The role of serotonergic antidepressants in reward

Antidepressants that selectively target the serotonergic system (SSRIs) have become the most widely prescribed pharmacotherapy for the treatment of major depression, since they were introduced in the late 1980s. SSRIs have been shown to be effective in alleviating symptoms of general distress in depression in 53%–64% of cases (Hirschfeld, 1999). However, core symptoms such as anhedonia, the loss of interest and decreased motivation are often unaffected by SSRI treatment (Nutt et al., 2007).

Discussion

The main aim of this review is to summarize studies that confirm an essential modulating role of the serotonergic system in reward processing. There is a great amount of anatomical evidence, demonstrating a tight connection between raphe nuclei in the brainstem and several cortical and subcortical areas implicated in reward processing. Although it is important to note that there are several neurotransmitters utilized in the raphe nuclei (Michelsen et al., 2007), their serotonergic projections

Conclusion

There is extensive data supporting an essential modulating role of the serotonergic system in major aspects of reward processing, as well as a change in serotonin transmission accompanied by rewarding activities. We therefore propose that serotonin may be a fundamental mediator of emotional, motivational and cognitive aspects of reward representation, which makes it possibly as important as dopamine for processing reward. However, some limitations have to be taken into account. First, complex

Acknowledgments

With special thanks to Markus Savli, Alexander Holik and Andreas Hahn for their support on the preparation of figures and to Dianne Lorenz for linguistic support. Furthermore, we thank Prof. Dr. Hans Herzog, Institut für Neurowissenschaften und Medizin (INM-4), Forschungszentrum Jülich, for providing the 5-HT2A maps. Dr. Kasper has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor, and Servier; has served as a consultant or on

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