The serotonin 2A (5-HT2A) receptor has been implicated in neural-processing of emotionally salient information. To elucidate its role in processing of fear and anger, healthy individuals were studied with functional magnetic resonance imaging (fMRI) after 5-HT2A receptor blockade, while judging the gender of neutral, fearful and angry faces.
Methods:
5-HT2A receptors were blocked with ketanserin to a variable degree across subjects by adjusting the time between ketanserin-infusion and onset of the fMRI protocol. Neocortical 5-HT2A receptor binding in terms of the binding potential (BPp) was assessed prior to fMRI with 18F-altanserin positron emission tomography (PET) and subsequently integrated in the fMRI data analysis. Also functional connectivity analysis was employed to evaluate the effect of ketanserin blocking on connectivity.
Results:
Compared to a control session, 5-HT2A receptor blockade reduced the neural response to fearful faces in the medial orbitofrontal cortex (OFC), independently of 5-HT2A receptor occupancy or neocortical 5-HT2A receptor BPp. The medial OFC also showed increased functional coupling with the left amygdala during processing of fearful faces depending on the amount of blocked 5-HT2A receptors.
Conclusions:
5-HT2A receptor mediated signaling increases the sensitivity of the OFC to fearful facial expressions and regulates the strength of a negative feedback signal from the OFC to amygdala during processing of fearful faces.
AdolphsR (2002) Recognizing emotion from facial expressions: Psychological and neurological mechanisms. Behav Cogn Neurosci Rev1: 21–62.
2.
BecharaADamasioHDamasioAR (2000) Emotion, decision making and the orbitofrontal cortex. Cereb Cortex10: 295–307.
3.
CoolsRRobertsACRobbinsTW (2007) Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn Sci12: 31–40.
4.
De GelderBMorrisJSDolanRJ (2005) Unconscious fear influences emotional awareness of faces and voices. PNAS102: 18682–18687.
5.
DeichmannRGottfriedJAHuttonC. (2003) Optimized EPI for fMRI studies of the orbitofrontal cortex. Neuroimage19: 430–441.
6.
EkmannP (1999) Basic emotions. In: DalgleishTPowerM (eds) Handbook of Cognition and Emotion. Sussex, UK: John Wiley and Sons, Ltd, pp. 45–60.
7.
ErritzoeDFrokjaerVGHaugbolS. (2009) Brain serotonin 2A receptor binding: Relations to body mass index, tobacco and alcohol use. Neuroimage46: 23–30.
8.
ErritzoeDHolstKFrokjaerVG. (2010) A nonlinear relationship between cerebral serotonin transporter and 5-HT(2A) receptor binding: An in vivo molecular imaging study in humans. J Neurosci30: 3391–3397.
9.
FairhallSLIshaiA (2007) Effective connectivity within the distributed cortical network for face perception. Cereb Cortex17: 2400–2406.
10.
FisherPMMeltzerCCPriceJC. (2009) Medial prefrontal cortex 5-HT2A density is correlated with amygdala reactivity, response habituation, and functional coupling. Cereb Cortex19: 2499–2507.
11.
ForsterGLFengNWattMJ. (2006) Corticotropin-releasing factor in the dorsal raphe elicits temporally distinct serotonergic responses in the limbic system in relation to fear behavior. Neuroscience141: 1047–1055.
12.
FristonKJBuechelCFinkGR. (1997) Psychophysiological and modulatory interactions in neuroimaging. Neuroimage6: 218–229.
13.
FrokjaerVGMortensenELNielsenFA. (2008) Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder. Biol Psychiatry63: 569–576.
14.
Fusar-PoliPPlacentinoACarlettiF. (2009) Functional atlas of emotional faces processing: A voxel-based meta-analysis of 105 functional magnetic resonance imaging studies. J Psychiatry Neurosci34: 418–432.
15.
GlennonRAMetwallyKDukatM. (2002) Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists. Curr Top Med Chem2: 539–558.
16.
GloverGHLiTQRessD (2000) Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn Reson Med44: 162–167.
17.
GradyCLSiebnerHRHornbøllB. (2013) Acute pharmacologically induced shifts in serotonin availability abolish emotion-selective responses to negative face emotions in distinct brain networks. Eur Neuropsychopharmacol23: 368–378.
18.
HarmerCJRogersRDTunbridgeE. (2003) Tryptophan depletion decreases the recognition of fear in female volunteers. Psychopharmacology (Berl)167: 411–417.
19.
HerrmannWMBaumgartnerP (1986) Combined pharmaco-EEG and pharmacopsychological study to estimate CNS effects of ketanserin in hypertensive patients. Neuropsychobiology16: 47–56.
20.
HornakJBramhamJRollsET. (2003) Changes in emotion after circumscribed surgical lesions of the orbitofrontal and cingulate cortices. Brain126: 1691–1712.
21.
HornakJRollsETWadeD (1996) Face and voice expression identification in patients with emotional and behavioural changes following ventral frontal lobe damage. Neuropsychologia34: 247–261.
22.
JakabRLGoldman-RakicPS (1998) 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci U S A95: 735–740.
23.
JakabRLGoldman-RakicPS (2000) Segregation of serotonin 5-HT2A and 5-HT3 receptors in inhibitory circuits of the primate cerebral cortex. J Comp Neurol417: 337–348.
24.
KorstanjeCSprenkelsRDoodsHN. (1986) Characterization of flufylline, fluprofylline, ritanserin, butanserin and R 56413 with respect to in-vivo alpha 1-,alpha 2- and 5-HT2-receptor antagonism and in-vitro affinity for alpha 1-,alpha 2- and 5-HT2-receptors: Comparison with ketanserin. J Pharm Pharmacol38: 374–379.
25.
KoudasVNikolaouAHourdakiE. (2009) Comparison of ketanserin, buspirone and propranolol on arousal, pupil size and autonomic function in healthy volunteers. Psychopharmacology (Berl)205: 1–9.
26.
KringelbachMLRollsET (2003) Neural correlates of rapid reversal learning in a simple model of human social interaction. Neuroimage20: 1371–1383.
27.
LancasterJLTordesillas-GutierrezDMartinezM. (2007) Bias between MNI and Talairach coordinates analyzed using the ICBM-152 brain template. Hum Brain Mapp28: 1194–1205.
28.
LiangXZebrowitzLAAharonI (2009) Effective connectivity between amygdala and orbitofrontal cortex differentiates the perception of facial expressions. Soc Neurosci4: 185–196.
29.
LundTEMadsenKHSidarosK. (2006) Non-white noise in fMRI: Does modelling have an impact?Neuroimage29: 54–66.
30.
LundqvistDFlyktAÖhmanA (1998) The Karolinska Directed Emotional Faces - KDEF [CD ROM]. Department of Clinical Neuroscience, Karolinska Institutet. ISBN 91-630-7164-9.
31.
McNairDMLorrMDropplemanLF (1971) Manual for the Profile of Mood States. San Diego, CA: Educational and Industrial Testing Services.
32.
MarnerLKnudsenGMHaugbolS. (2009) Longitudinal assessment of cerebral 5-HT2A receptors in healthy elderly volunteers: An [18F]-altanserin PET study. Eur J Nucl Med Mol Imaging36: 287–293.
33.
MaybergHS (2003) Modulating dysfunctional limbic-cortical circuits in depression: Towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull65: 193–207.
34.
Muller-GartnerHWLinksJMPrinceJL. (1992) Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects. J Cereb Blood Flow Metab12: 571–583.
OlsenKSVidebaekCSchmidtJF. (1992) The effect of ketanserin on cerebral blood flow and cerebrovascular CO2 reactivity in healthy volunteers. Acta Neurochir (Wien)119: 7–11.
37.
PassamontiLCrockettMJApergis-SchouteAM. (2012) Effects of acute tryptophan depletion on prefrontal-amygdala connectivity while viewing facial signals of aggression. Biol Psychiatry71: 36–43.
38.
PaulmannSSeifertSKotzSA (2010) Orbito-frontal lesions cause impairment during late but not early emotional prosodic processing. Soc Neurosci5: 59–75.
39.
PhillipsMLDrevetsWCRauchSL. (2003) Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biol Psychiatry54: 515–528.
40.
PinborgLHAdamsKHSvarerC. (2003) Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metab23: 985–996.
41.
QuarantelliMBerkoukKPrinsterA. (2004) Integrated software for the analysis of brain PET/SPECT studies with partial-volume-effect correction. J Nucl Med45: 192–201.
42.
SalzmanCDFusiS (2010) Emotion, cognition, and mental state representation in amygdala and prefrontal cortex. Annu Rev Neurosci33: 173–202.
43.
SteinJLWiedholzLMBassettDS. (2007) A validated network of effective amygdala connectivity. Neuroimage36: 736–745.
44.
SvarerCMadsenKHasselbalchSG. (2005) MR-based automatic delineation of volumes of interest in human brain PET images using probability maps. Neuroimage24: 969–979.
WillisMLPalermoRBurkeD. (2010) Orbitofrontal cortex lesions result in abnormal social judgements to emotional faces. Neuropsychologia48: 2182–2187.
47.
WingenMKuypersKPRamaekersJG (2007) The role of 5-HT1a and 5-HT2a receptors in attention and motor control: A mechanistic study in healthy volunteers. Psychopharmacology (Berl)190: 391–400.
