Serotonin has long been implicated in emotional processing, but its specific mechanism of action is unclear. In this review we briefly summarise current perspectives on the neurobiological role of serotonin at the behavioural, cognitive and neural levels. We provide a general overview of serotonergic molecular pathways before discussing behavioural research delineating a role of serotonin in aversive inhibition. We then outline recent attempts to computationally formalise this role in aversive inhibition at the cognitive level. Finally, we try to situate these effects within neural circuitry. We argue, in particular, that the computational role of serotonin in aversive inhibition may be underpinned by serotonergic inhibition of prefrontal-amygdala circuits. Working to refine and improve our understanding of the neurobiological basis of serotonergic function is critical in order to improve our ability to diagnose and treat psychiatric disorders such as depression and anxiety in which serotonin may play a central role.
BeddingtonJ., CooperC. L., FieldJ., GoswamiU., HuppertF. A., JenkinsR., JonesH. S., KirkwoodT. B. L., SahakianB. J., and ThomasS. M. (2008). “The mental wealth of nations.”Nature455(7216): 1057-1060. http://dx.doi.org/10.1038/4551057a
5.
BevilacquaL., DolyS., KaprioJ., YuanQ., TikkanenR., PaunioT., ZhouZ., WedenojaJ., MaroteauxL., DiazS., BelmerA., HodgkinsonC. A., Dell/'OssoL., SuvisaariJ., CoccaroE., RoseR. J., PeltonenL., VirkkunenM., and GoldmanD. (2010). “A population-specific HTR2B stop codon predisposes to severe impulsivity.”Nature468(7327): 1061-1066. http://dx.doi.org/10.1038/nature09629
6.
BlakelyR. D., BersonH. E., FremeauR. T., CaronM. G., PeekM. M., PrinceH. K., and BradleyC. C. (1991). “Cloning and expression of a functional serotonin transporter from rat brain.”Nature354(6348): 66-70. http://dx.doi.org/10.1038/354066a0
7.
BrowningM., HolmesE., and HarmerC. (2010). “The modification of attentional bias to emotional information: A review of the techniques, mechanisms, and relevance to emotional disorders.”Cognitive, Affective, & Behavioral Neuroscience10(1): 8-20. http://dx.doi.org/10.3758/CABN.10.1.8
8.
ClarkL., RoiserJ., CoolsR., SahakianB., and RobbinsT. (2005). “Acute tryptophan depletion and the 5-HT transporter polymorphism do not modulate stop signal response inhibition.”Journal of Cognitive Neuroscience: 88-88.
9.
ClarkeH. F., DalleyJ. W., CroftsH. S., RobbinsT. W., and RobertsA. C. (2004). “Cognitive Inflexibility After Prefrontal Serotonin Depletion.”Science304(5672): 878-880. http://dx.doi.org/10.1126/science.1094987
10.
CoolsR., RobertsA. C., and RobbinsT. W. (2008). “Serotoninergic regulation of emotional and behavioural control processes.”Trends in Cognitive Sciences12(1): 31-40. http://dx.doi.org/10.1016/j.tics.2007.10.011
11.
CoolsR., RobinsonO. J., and SahakianB. (2008). “Acute Tryptophan Depletion in Healthy Volunteers Enhances Punishment Prediction but Does not Affect Reward Prediction.”Neuropsychopharmacology33(9): 2291-2299. http://dx.doi.org/10.1038/sj.npp.1301598
12.
CreanJ., RichardsJ. B., and de WitH. (2002). “Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism.”Behavioural Brain Research136(2): 349-357. http://dx.doi.org/10.1016/S0166-4328(02)00132-8
13.
CrockettM. J., ClarkL., and RobbinsT. W. (2009). “Reconciling the Role of Serotonin in Behavioral Inhibition and Aversion: Acute Tryptophan Depletion Abolishes Punishment-Induced Inhibition in Humans.”The Journal of Neuroscience29(38): 11993-11999. http://dx.doi.org/10.1523/JNEUROSCI.2513-09.2009
14.
CrockettM. J., ClarkL., RoiserJ. P., RobinsonO. J., CoolsR., ChaseH. W., den OudenH., Apergis-SchouteA., Campbell-MeikeljohnD., SeymourB., SahakianB. J., RogersR. D., and RobbinsT. W. (2011). “Converging evidence for central 5-HT effects in acute tryptophan depletion.”Mol Psychiatry.
DavisM., WalkerD. L., MilesL., and GrillonC. (2010). “Phasic vs Sustained Fear in Rats and Humans: Role of the Extended Amygdala in Fear vs Anxiety.”Neuropsychopharmacology35(1): 105-135. http://dx.doi.org/10.1038/npp.2009.109
DescarriesL., and RiadM. (2012). “Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT.”Philosophical Transactions of the Royal Society B: Biological Sciences367(1601): 2416-2425. http://dx.doi.org/10.1098/rstb.2011.0361
20.
Di SimplicioM., NorburyR., ReineckeA., and HarmerC. J. (2014). “Paradoxical effects of short-term antidepressant treatment in fMRI emotional processing models in volunteers with high neuroticism.”Psychological Medicine44(02): 241-252. http://dx.doi.org/10.1017/S0033291713000731
21.
EagleD. M., LehmannO., TheobaldD. E. H., PenaY., ZakariaR., GhoshR., DalleyJ. W., and RobbinsT. W. (2008). “Serotonin Depletion Impairs Waiting but not Stop-Signal Reaction Time in Rats: Implications for Theories of the Role of 5-HT in Behavioral Inhibition.”Neuropsychopharmacology34(5): 1311-1321. http://dx.doi.org/10.1038/npp.2008.202
22.
ElliottR., RubinszteinJ. S., SahakianB. J., and DolanR. J. (2002). “The Neural Basis of Mood-Congruent Processing Biases in Depression.”Archives of General Psychiatry59(7): 597-604. http://dx.doi.org/10.1001/archpsyc.59.7.597
FakraE., HydeL. W., GorkaA., and (2009). “EFfects of htr1a c(-1019)g on amygdala reactivity and trait anxiety.”Archives of General Psychiatry66(1): 33-40. http://dx.doi.org/10.1001/archpsyc.66.1.33
25.
FisherP., PriceJ., MeltzerC., Moses-KolkoE., BeckerC., BergaS., and HaririA. (2011). “Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity.”Biology of Mood & Anxiety Disorders1(1): 2. http://dx.doi.org/10.1186/2045-5380-1-2
26.
FisherP. M., MeltzerC. C., PriceJ. C., ColemanR. L., ZiolkoS. K., BeckerC., Moses-KolkoE. L., BergaS. L., and HaririA. R. (2009). “Medial Prefrontal Cortex 5-HT2A Density Is Correlated with Amygdala Reactivity, Response Habituation, and Functional Coupling.”Cerebral Cortex19(11): 2499-2507. http://dx.doi.org/10.1093/cercor/bhp022
27.
FisherP. M., MeltzerC. C., ZiolkoS. K., PriceJ. C., and HaririA. R. (2006). “Capacity for 5-HT1A-mediated autoregulation predicts amygdala reactivity.”Nat Neurosci9(11): 1362-1363. http://dx.doi.org/10.1038/nn1780
28.
FoxE., RidgewellA., and AshwinC. (2009). “Looking on the bright side: biased attention and the human serotonin transporter gene.”Proceedings of the Royal Society B: Biological Sciences276(1663): 1747-1751. http://dx.doi.org/10.1098/rspb.2008.1788
29.
GellynckE., HeyninckK., AndressenK., HaegemanG., LevyF., VanhoenackerP., and Van CraenenbroeckK. (2013). “The serotonin 5-HT7 receptors: two decades of research.”Experimental Brain Research: 1-14. http://dx.doi.org/10.1007/s00221-013-3694-y
30.
GrillonC., AmeliR., WoodsS. W., MerikangasK., and DavisM. (1991). “Fear-Potentiated Startle in Humans: Effects of Anticipatory Anxiety on the Acoustic Blink Reflex.”Psychophysiology28(5): 588-595. http://dx.doi.org/10.1111/j.1469-8986.1991.tb01999.x
31.
GrillonC., ChavisC., CovingtonM. F., and PineD. S. (2008). “Two-week treatment with the selective serotonin reuptake inhibitor citalopram reduces contextual anxiety but not cued fear in healthy volunteers: a fear-potentiated startle study.”Neuropsychopharmacology34(4): 964-971. http://dx.doi.org/10.1038/npp.2008.141
32.
GrillonC., LevensonJ., and PineD. S. (2006). “A Single Dose of the Selective Serotonin Reuptake Inhibitor Citalopram Exacerbates Anxiety in Humans: A Fear-Potentiated Startle Study.”Neuropsychopharmacology32(1): 225-231. http://dx.doi.org/10.1038/sj.npp.1301204
33.
HaririA. R., and HolmesA. (2006). “Genetics of emotional regulation: the role of the serotonin transporter in neural function.”Trends in Cognitive Sciences10(4): 182-191. http://dx.doi.org/10.1016/j.tics.2006.02.011
34.
HarmerC. J. (2008). “Serotonin and emotional processing: Does it help explain antidepressant drug action?”Neuropharmacology doi: 10.1016/j.neuropharm.2008.06.036. http://dx.doi.org/10.1016/j.neuropharm.2008.06.036
35.
HarmerC. J., BhagwagarZ., PerrettD. I., VöllmB. A., CowenP. J., and GoodwinG. M. (2003). “Acute SSRI administration affects the processing of social cues in healthy volunteers.”Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology28(1): 148-152. http://dx.doi.org/10.1038/sj.npp.1300004
36.
HarmerC. J., CowenP. J., and GoodwinG. M. (2011). “Efficacy markers in depression.”Journal of Psychopharmacology25(9): 1148-1158. http://dx.doi.org/10.1177/0269881110367722
37.
HarmerC. J., GoodwinG. M., and CowenP. J. (2009). “Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action.”The British Journal of Psychiatry195(2): 102-108. http://dx.doi.org/10.1192/bjp.bp.108.051193
38.
HarmerC. J., HillS. A., TaylorM. J., CowenP. J., and GoodwinG. M. (2003). “Toward a neuropsychological theory of antidepressant drug action: Increase in positive emotional bias after potentiation of norepinephrine activity.”American Journal of Psychiatry160(5): 990-992. http://dx.doi.org/10.1176/appi.ajp.160.5.990
39.
HarmerC. J., MackayC. E., ReidC. B., CowenP. J., and GoodwinG. M. (2006). “Antidepressant Drug Treatment Modifies the Neural Processing of Nonconscious Threat Cues.”Biological Psychiatry59(9): 816-820. http://dx.doi.org/10.1016/j.biopsych.2005.10.015
40.
HarrisonA. A., EverittB. J., and RobbinsT. W. (1999). “Central serotonin depletion impairs both the acquisition and performance of a symmetrically reinforced go/no-go conditional visual discrimination.”Behav Brain Res100(1-2): 99-9112. http://dx.doi.org/10.1016/S0166-4328(98)00117-X
41.
HazraR., GuoJ. D., DabrowskaJ., and RainnieD. G. (2012). “Differential distribution of serotonin receptor subtypes in BNSTALG neurons: Modulation by unpredictable shock stress.”Neuroscience225(0): 9-21. http://dx.doi.org/10.1016/j.neuroscience.2012.08.014
42.
HuysQ. J. M., EshelN., O'NionsE., SheridanL., DayanP., and RoiserJ. P. (2012). “Bonsai Trees in Your Head: How the Pavlovian System Sculpts Goal-Directed Choices by Pruning Decision Trees.”PLoS Comput Biol8(3): e1002410. http://dx.doi.org/10.1371/journal.pcbi.1002410
43.
LanzenbergerR., KranzG. S., HaeuslerD., AkimovaE., SavliM., HahnA., MitterhauserM., SpindeleggerC., PhilippeC., FinkM., WadsakW., KaranikasG., and KasperS. (2012). “Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas.”Neuroimage63(2): 874-881. http://dx.doi.org/10.1016/j.neuroimage.2012.07.023
44.
LeMarquandD. G., BenkelfatC., PihlR. O., PalmourR. M., and YoungS. N. (1999). “Behavioral Disinhibition Induced by Tryptophan Depletion in Nonalcoholic Young Men With Multigenerational Family Histories of Paternal Alcoholism.”American Journal of Psychiatry156(11): 1771-1779.
McCabeC., MishorZ., CowenP. J., and HarmerC. J. (2010). “Diminished Neural Processing of Aversive and Rewarding Stimuli During Selective Serotonin Reuptake Inhibitor Treatment.”Biological Psychiatry67(5): 439-445. http://dx.doi.org/10.1016/j.biopsych.2009.11.001
47.
McCabeC., MishorZ., FilippiniN., CowenP. J., TaylorM. J., and HarmerC. J. (2011). “SSRI administration reduces resting state functional connectivity in dorso-medial prefrontal cortex.”Mol Psychiatry16(6): 592-594. http://dx.doi.org/10.1038/mp.2010.138
48.
MoggK., and BradleyB. (2005). “Attentional Bias in Generalized Anxiety Disorder Versus Depressive Disorder.”Cognitive Therapy and Research29(1): 29-45. http://dx.doi.org/10.1007/s10608-005-1646-y
MurphyF. C., SmithK. A., CowenP. J., RobbinsT. W., and SahakianB. J. (2002). “The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers.”Psychopharmacology163(1): 42-53. http://dx.doi.org/10.1007/s00213-002-1128-9
51.
NorburyR., MackayC. E., CowenP. J., GoodwinG. M., and HarmerC. J. (2007). “Short-term antidepressant treatment and facial processing: Functional magnetic resonance imaging study.”British Journal of Psychiatry190(JUNE): 531-532.
52.
O'NionsE. J. P., DolanR. J., and RoiserJ. P. (2011). “Serotonin Transporter Genotype Modulates Subgenual Response to Fearful Faces Using an Incidental Task.”Journal of Cognitive Neuroscience23(11): 3681-3693. http://dx.doi.org/10.1162/jocn_a_00055
53.
PassamontiL., CrockettM. J., Apergis-SchouteA. M., ClarkL., RoweJ. B., CalderA. J., and RobbinsT. W. (2012). “Effects of Acute Tryptophan Depletion on Prefrontal-Amygdala Connectivity While Viewing Facial Signals of Aggression.”Biological Psychiatry71(1): 36-43. http://dx.doi.org/10.1016/j.biopsych.2011.07.033
54.
PezawasL., Meyer-LindenbergA., DrabantE. M., VerchinskiB. A., MunozK. E., KolachanaB. S., EganM. F., MattayV. S., HaririA. R., and WeinbergerD. R. (2005). “5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression.”Nat Neurosci8(6): 828-834. http://dx.doi.org/10.1038/nn1463
55.
ReineckeA., CooperM., FavaronE., Massey-ChaseR., and HarmerC. (2011). “Attentional bias in untreated panic disorder.”Psychiatry Research185(3): 387-393. http://dx.doi.org/10.1016/j.psychres.2010.07.020
56.
RobinsonO. J., CharneyD. R., OverstreetC., VytalK., and GrillonC. (2012). “The adaptive threat bias in anxiety: Amygdala–dorsomedial prefrontal cortex coupling and aversive amplification.”Neuroimage60(1): 523-529. http://dx.doi.org/10.1016/j.neuroimage.2011.11.096
57.
RobinsonO. J., CoolsR., and SahakianB. J. (2012). “Tryptophan depletion disinhibits punishment but not reward prediction: implications for resilience.”Psychopharmacology (Berl)219(2): 599-605. http://dx.doi.org/10.1007/s00213-011-2410-5
58.
RobinsonO. J., OverstreetC., AllenP. S., LetkiewiczA., VytalK., PineD. S., and GrillonC. (2013). “The role of serotonin in the neurocircuitry of negative affective bias: Serotonergic modulation of the dorsal medial prefrontal-amygdala ‘aversive amplification’ circuit.”Neuroimage78(0): 217-223. http://dx.doi.org/10.1016/j.neuroimage.2013.03.075
59.
RobinsonO. J., OverstreetC., AllenP. S., PineD. S., and GrillonC. (2012). “Acute Tryptophan Depletion Increases Translational Indices of Anxiety but not Fear: Serotonergic Modulation of the Bed Nucleus of the Stria Terminalis[quest].”Neuropsychopharmacology37(8): 1963-1971. http://dx.doi.org/10.1038/npp.2012.43
60.
RoiserJ. P., BlackwellA. D., CoolsR., ClarkL., RubinszteinD. C., RobbinsT. W., and SahakianB. J. (2006). “Serotonin Transporter Polymorphism Mediates Vulnerability to Loss of Incentive Motivation Following Acute Tryptophan Depletion.”Neuropsychopharmacology31(10): 2264-2272. http://dx.doi.org/10.1038/sj.npp.1301084
61.
RoiserJ. P., ElliottR., and SahakianB. J. (2012). “Cognitive Mechanisms of Treatment in Depression.”Neuropsychopharmacology37(1): 117-136. http://dx.doi.org/10.1038/npp.2011.183
62.
RoiserJ. P., LevyJ., FrommS. J., GoldmanD., HodgkinsonC. A., HaslerG., SahakianB. J., and DrevetsW. C. (2012). “Serotonin transporter genotype differentially modulates neural responses to emotional words following tryptophan depletion in patients recovered from depression and healthy volunteers.”Journal of Psychopharmacology26(11): 1434-1442. http://dx.doi.org/10.1177/0269881112442789
63.
RoiserJ. P., LevyJ., FrommS. J., NugentA. C., TalagalaS. L., HaslerG., HennF. A., SahakianB. J., and DrevetsW. C. (2009). “The Effects of Tryptophan Depletion on Neural Responses to Emotional Words in Remitted Depression.”Biological Psychiatry66(5): 441-450. http://dx.doi.org/10.1016/j.biopsych.2009.05.002
SchmitzA., and GrillonC. (2012). “Assessing fear and anxiety in humans using the threat of predictable and unpredictable aversive events (the NPU-threat test).”Nat. Protocols7(3): 527-532. http://dx.doi.org/10.1038/nprot.2012.001
66.
SelvarajS., TurkheimerF., RossoL., FaulknerP., MouchlianitisE., RoiserJ. P., McGuireP., CowenP. J., and HowesO. (2012). “Measuring endogenous changes in serotonergic neurotransmission in humans: a [11C]CUMI-101 PET challenge study.”Mol Psychiatry17(12): 1254-1260. http://dx.doi.org/10.1038/mp.2012.78
67.
SmithH. R., DaunaisJ. B., NaderM. A., and PorrinoL. J. (1999). “Distribution of [3H]Citalopram Binding Sites in the Nonhuman Primate Brain.”Annals of the New York Academy of Sciences877(1): 700-702. http://dx.doi.org/10.1111/j.1749-6632.1999.tb09305.x
68.
SoubrieP. (1986). “Reconciling the role of central serotonin neurons in human and animal behavior.”Behav Brain Sci9(2): 319-335. http://dx.doi.org/10.1017/S0140525X00022871
69.
van der VeenF. M., EversE. A. T., DeutzN. E. P., and SchmittJ. A. J. (2007). “Effects of acute tryptophan depletion on mood and facial emotion perception related brain activation and performance in healthy women with and without a family history of depression.”Neuropsychopharmacology32(1): 216-224. http://dx.doi.org/10.1038/sj.npp.1301212
70.
VictorT. A., FureyM. L., FrommS. J., BellgowanP. S. F., ÖhmanA., and DrevetsW. C. (2012). “The Extended Functional Neuroanatomy of Emotional Processing Biases for Masked Faces in Major Depressive Disorder.”PLoS ONE7(10): e46439. http://dx.doi.org/10.1371/journal.pone.0046439
71.
VictorT. A., FureyM. L., FrommS. J., ÖhmanA., and DrevetsW. C. (2010). “RElationship between amygdala responses to masked faces and mood state and treatment in major depressive disorder.”Archives of General Psychiatry67(11): 1128-1138. http://dx.doi.org/10.1001/archgenpsychiatry.2010.144
