Serotonergic Modulation of Conditioned Fear

Abstract

Conditioned fear plays a key role in anxiety disorders as well as depression and other neuropsychiatric conditions. Understanding how neuromodulators drive the associated learning and memory processes, including memory consolidation, retrieval/expression, and extinction (recall), is essential in the understanding of (individual differences in vulnerability to) these disorders and their treatment. The human and rodent studies I review here together reveal, amongst others, that acute selective serotonin reuptake inhibitor (SSRI) treatment facilitates fear conditioning, reduces contextual fear, and increases cued fear, chronic SSRI treatment reduces both contextual and cued fear, 5-HT1A receptors inhibit the acquisition and expression of contextual fear, 5-HT2A receptors facilitates the consolidation of cued and contextual fear, inactivation of 5-HT2C receptors facilitate the retrieval of cued fear memory, the 5-HT3 receptor mediates contextual fear, genetically induced increases in serotonin levels are associated with increased fear conditioning, impaired cued fear extinction, or impaired extinction recall, and that genetically induced 5-HT depletion increases fear conditioning and contextual fear. Several explanations are presented to reconcile seemingly paradoxical relationships between serotonin levels and conditioned fear.

The relation between infant freezing and the development of internalizing symptoms in adolescence: A prospective longitudinal study

“…In line with this work, our explorative analysis suggests that S′‐homozygotes of 5‐HTTLPR/ rs25531 show more deviant freezing than L′‐carriers. This finding suggests a similar genetic basis of alterations in human freezing as previously reported for animals (Bethea et al., ; Homberg, ). However, 5‐HTTLPR/ rs25531 polymorphism did not moderate the association between freezing and internalizing symptoms in this study, suggesting that freezing—although related to 5‐HTTLPR/ rs25531—is independently associated with internalizing symptoms.…”

“…We explored the role of genetic variation in serotonin signaling in deviant freezing, as seen in animals (Homberg, ). First, we explored whether 5‐HTTLPR /rs25531 genotype (S′‐homozygotes vs L′‐carriers [L′/L′ and L′/S′ combined]) could predict infant freezing in a linear fashion, which was not the case (estimate = 0.00, t = −0.04, p > 0.250).…”

“…Finally, in line with the role of serotonin in freezing, genetic variation in the gene encoding the serotonin transporter ( SLC6A4 ) has been associated with altered freezing and increased vulnerability to develop internalizing symptoms in animals (Bethea et al., ; Homberg, ). In humans, variations in SLC6A4/5‐HTT/SERT have been linked to depression, especially in conjunction with stress (Bleys, Luyten, Soenens, & Claes, ).…”

Chronic fluoxetine dissociates contextual from auditory fear memory

“…Stimulating auto-inhibitory 5-HT1A receptors in the median raphe nucleus also causes decreased contextual freezing [43, 44]. Therefore, as previously proposed [32], it may be that SSRI treatment increases synaptic serotonin levels to stimulate 5-HT1A, and to decrease contextual freezing. Alternatively, fluoxetine is a 5-HT2C receptor antagonist [28].…”

“…While the serotonergic modulation of fear memory has been extensively studied [27, 32–37], these experiments are the first to examine the effects of chronic, preconditioning fluoxetine on both the contextual and auditory fear memory of mice. Using two differing experimental paradigms, the fluoxetine treatment of adult mice impaired their contextual fear memory, but spared auditory fear memory.…”