ReviewSerotonin in fear conditioning processes
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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