Review
Cognitive-emotional interactions
Serotoninergic regulation of emotional and behavioural control processes

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5-Hydroxytryptamine (5-HT, serotonin) has long been implicated in a wide variety of emotional, cognitive and behavioural control processes. However, its precise contribution is still not well understood. Depletion of 5-HT enhances behavioural and brain responsiveness to punishment or other aversive signals, while disinhibiting previously rewarded but now punished behaviours. Findings suggest that 5-HT modulates the impact of punishment-related signals on learning and emotion (aversion), but also promotes response inhibition. Exaggerated aversive processing and deficient response inhibition could underlie distinct symptoms of a range of affective disorders, namely stress- or threat-vulnerability and compulsive behaviour, respectively. We review evidence from studies with human volunteers and experimental animals that begins to elucidate the neurobiological systems underlying these different effects.

Section snippets

The paradox of 5-HT

Of the central monoamine neurotransmitters, 5-hydroxytryptamine (5-HT, or serotonin) presents perhaps the greatest challenge in terms of deducing its main role; even when considering its modulatory effect on behaviour and cognition it is difficult to discern one single principle underlying its actions. This is not surprising given the diversity of its neuroanatomical ramifications from the midbrain dorsal and median raphé nuclei (DRN and MRN) to virtually all regions of the brain (Figure 1),

5-HT: threat, punishment and aversive learning

Enhanced sensitivity to threat-related stimuli and punishment is a cardinal feature of several mood and anxiety disorders that implicate central 5-HT systems 10, 11, 12, 13, 14. Consistent with this observation are findings that 5-HT modulates the responsiveness of the amygdala and connected medial frontal regions to threat-related stimuli in humans and animals; Table 1 summarizes the effects reviewed below 15, 16, 17, 18, 19.

Inhibitory response control

The hypothesis that 5-HT has a major role in behavioural inhibition has a long history, which has run somewhat parallel and counter to the hypothesis that 5-HT modulates biases towards aversive processing. There are many different forms of inhibition [48] occurring at both cortical [49] and subcortical levels [50] that could be affected by 5-HT, including, for example, Pavlovian conditioned inhibition (see Glossary). Reductions in 5-HT function increase appetitive responding for reward in

Concluding remarks

These findings highlight the paradox outlined in our opening paragraphs, namely that a release of punished responding following reduced serotoninergic transmission is in apparent direct contrast to the enhanced responsiveness to and prediction of aversive stimuli reviewed above.

How to resolve this paradox? One might argue that the experimental analysis is incomplete and the comparisons might not pay sufficient attention to the different methods that are used; for example, ATD produces a mild

Acknowledgements

This work was conducted within the Behavioural and Clinical Neuroscience Institute at the University of Cambridge, cofunded by the Medical Research Council and the Wellcome Trust. R.C. was supported by a Royal Society University Research fellowship.

Glossary

Anxiolytic
Reducing anxiety, or an agent that reduces anxiety.
Discrete cue fear conditioning
The process by which a neutral stimulus (e.g. a tone) becomes associated with an aversive stimulus (e.g. a footshock) thus acquiring the capacity to elicit a defensive response (e.g. freezing).
Pavlovian conditioned inhibition
The suppression of appetitive responding (for reward) on the presentation of a conditioned stimulus (e.g. light) that predicts an aversive signal (e.g. shock).
Phasic neurotransmission

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