Elsevier

Behavioural Brain Research

Volume 277, 15 January 2015, Pages 68-77
Behavioural Brain Research

Review
Serotonin in fear conditioning processes

https://doi.org/10.1016/j.bbr.2014.07.028Get rights and content

Highlights

  • 5-HT2A agonists are anxiogenic and enhance fear learning.

  • 5-HT1A agonists are anxiolytic and impair cued and contextual fear learning.

  • Variation in 5-HT genes can influence fear conditioning and extinction.

  • Roles of the amygdala, hippocampus and BNST in mediating acute SSRI effects.

Abstract

This review describes the latest developments in our understanding of how the serotonergic system modulates Pavlovian fear conditioning, fear expression and fear extinction. These different phases of classical fear conditioning involve coordinated interactions between the extended amygdala, hippocampus and prefrontal cortices. Here, I first define the different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. The serotonergic system can be manipulated by administering serotonin receptor agonists and antagonists, as well as selective serotonin reuptake inhibitors (SSRIs), and these can have significant effects on emotional learning and memory. Moreover, variations in serotonergic genes can influence fear conditioning and extinction processes, and can underlie differential responses to pharmacological manipulations. This research has considerable translational significance as imbalances in the serotonergic system have been linked to anxiety and depression, while abnormalities in the mechanisms of conditioned fear contribute to anxiety disorders.

Introduction

One hallmark of several anxiety disorders is an abnormality in acquiring or extinguishing conditioned fear memories [1], [2]. Manipulations of the serotonin (5-HT) system are widely used to treat a variety of anxiety disorders such as panic disorder, social phobia, generalized anxiety disorder and obsessive-compulsive disorder [3], [4], [5], [6], [7]. Thus, an understanding of how the serotonergic system modulates fear learning processes has been of considerable interest for decades. The advantage of studying classical Pavlovian fear conditioning is that it is a model of emotional learning for which the underlying neural circuitry has been described in detail. The structures involved in fear learning and expression, including the amygdala, hippocampus and prefrontal cortices, contain dense concentrations of 5-HT receptors [8], [9], [10]. Moreover, 5-HT levels in the amygdala increase during both cued and context fear conditioning [11], [12], [13]. Here, recent advances in our understanding of the neural circuits involved in fear learning, expression and extinction are described. I then review the literature describing how manipulations of the serotonergic system affect each of these behavioral processes, attempt to reconcile seemingly contradictory findings and offer recommendations for future research.

Section snippets

The neural circuitry underlying classical fear conditioning

Pavlovian fear conditioning is one of the most comprehensively studied behavioral paradigms. In classical fear conditioning, an initially neutral stimulus, such as a tone or light (conditioned stimulus; CS) is paired with an aversive stimulus, such as a brief electrical footshock (unconditioned stimulus; US). As a result of this pairing, the CS acquires aversive properties. Afterwards, when presented alone, the CS elicits responses in the animal that are characteristic of fear, including

Serotonergic modulation of fear learning and expression

Fear learning and extinction are thus mediated by interactions between several nuclei of the amygdala, the hippocampus, the mPFC and the BNST. All of these structures contain dense concentrations of 5-HT receptors [8], [9], [10]. Moreover, there is an increase in the concentration of amygdalar 5-HT both during and after behavioral arousal and stress and in response to US presentations during fear conditioning [12], [13], [86], [87], [88]. After context fear conditioning, there are increases in

Serotonin transporter gene variation

Variations in serotonergic genes can influence fear conditioning and extinction processes. The most widely studied is a functional polymorphism in the promotor region of the 5-HT transporter gene (5-HTTPR). The 5-HT transporter 5-HTT regulates 5-HT signaling via reuptake of 5-HT from the extracellular space [154]. In humans, the short (s) allele of the 5-HTT promotor region, which is associated with decreased transcription of the gene compared to the long (l) allele, leads to reduced 5-HTT

Acute SSRI administration and fear conditioning

SSRIs, such as citalopram, escitalopram, fluoxetine, fluvoxamine and paroxetine are widely used for the treatment of anxiety disorders including panic disorder, generalized anxiety disorder, phobias and obsessive-compulsive disorder [4], [6], [176], [177]. SSRIs act pharmacologically by inhibiting the serotonin transporter, leading to an increase in 5-HT availability. These increased levels of 5-HT produce an increase in anxiety that can be measured in animals using a variety of behavioral

Serotonin depletion

Lastly, reducing central 5-HT levels and examining the effects on fear conditioning can also provide insights into the normal role of 5-HT in this behavioral paradigm. 5-HT can be reduced throughout the brain in several ways. One method is acute tryptophan depletion, which deprives the subject of the precursor of 5-HT [221] and decreases the release of 5-HT [222], [223]. Another is to interfere with the synthesis of 5-HT by systemic or local injection of p-chlorophenylalanine (PCPA) which

Conclusions

A considerable body of literature has examined how modulation of the serotonergic system affects Pavlovian fear conditioning and extinction. Strategies for manipulating this system include the administration of agonists or antagonists directed against one of the 17 different 5-HT receptor subtypes, administration of SSRIs and serotonin depletion. Moreover, there is considerable genetic variation among individuals resulting in altered functionality of the 5-HT transporter. Given the complex, and

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