Acute serotonin 2A receptor blocking alters the processing of fearful faces in the orbitofrontal cortex and amygdala

Background: 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.

[1]  C. Grady,et al.  Acute pharmacologically induced shifts in serotonin availability abolish emotion-selective responses to negative face emotions in distinct brain networks , 2013, European Neuropsychopharmacology.

[2]  T. Robbins,et al.  Effects of Acute Tryptophan Depletion on Prefrontal-Amygdala Connectivity While Viewing Facial Signals of Aggression , 2012, Biological Psychiatry.

[3]  Stefano Fusi,et al.  Emotion, cognition, and mental state representation in amygdala and prefrontal cortex. , 2010, Annual review of neuroscience.

[4]  D. Burke,et al.  Orbitofrontal cortex lesions result in abnormal social judgements to emotional faces , 2010, Neuropsychologia.

[5]  Claus Svarer,et al.  A Nonlinear Relationship between Cerebral Serotonin Transporter and 5-HT2A Receptor Binding: An In Vivo Molecular Imaging Study in Humans , 2010, The Journal of Neuroscience.

[6]  Sebastian Seifert,et al.  Orbito-frontal lesions cause impairment during late but not early emotional prosodic processing , 2010, Social neuroscience.

[7]  P. McGuire,et al.  Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies. , 2009, Journal of psychiatry & neuroscience : JPN.

[8]  P. Cowen,et al.  Short-term antidepressant treatment modulates amygdala response to happy faces , 2009, Psychopharmacology.

[9]  Olaf B. Paulson,et al.  Brain serotonin 2A receptor binding: Relations to body mass index, tobacco and alcohol use , 2009, NeuroImage.

[10]  P. Roussos,et al.  Comparison of ketanserin, buspirone and propranolol on arousal, pupil size and autonomic function in healthy volunteers , 2009, Psychopharmacology.

[11]  Leslie A. Zebrowitz,et al.  Effective connectivity between amygdala and orbitofrontal cortex differentiates the perception of facial expressions , 2009, Social neuroscience.

[12]  Patrick M. Fisher,et al.  FEATURE ARTICLE Medial Prefrontal Cortex 5-HT2A Density Is Correlated with Amygdala Reactivity, Response Habituation, and Functional Coupling , 2009 .

[13]  Søren Holm,et al.  Longitudinal assessment of cerebral 5-HT2A receptors in healthy elderly volunteers: an [18F]-altanserin PET study , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[14]  Olaf B. Paulson,et al.  Frontolimbic Serotonin 2A Receptor Binding in Healthy Subjects Is Associated with Personality Risk Factors for Affective Disorder , 2008, Biological Psychiatry.

[15]  T. Robbins,et al.  Serotoninergic regulation of emotional and behavioural control processes , 2008, Trends in Cognitive Sciences.

[16]  Michael J. Martinez,et al.  Bias between MNI and Talairach coordinates analyzed using the ICBM‐152 brain template , 2007, Human brain mapping.

[17]  A. Ishai,et al.  Effective connectivity within the distributed cortical network for face perception. , 2007, Cerebral cortex.

[18]  Danielle S. Bassett,et al.  A validated network of effective amygdala connectivity , 2007, NeuroImage.

[19]  R. Deichmann,et al.  Optimized EPI for fMRI studies of the orbitofrontal cortex: compensation of susceptibility-induced gradients in the readout direction , 2007, Magnetic Resonance Materials in Physics, Biology and Medicine.

[20]  C. H. Summers,et al.  Corticotropin-releasing factor in the dorsal raphe elicits temporally distinct serotonergic responses in the limbic system in relation to fear behavior , 2006, Neuroscience.

[21]  J. John Mann,et al.  Cortical 5-HT2A Receptor Signaling Modulates Anxiety-Like Behaviors in Mice , 2006, Science.

[22]  Thomas E. Nichols,et al.  Non-white noise in fMRI: Does modelling have an impact? , 2006, NeuroImage.

[23]  J. Ramaekers,et al.  The role of 5-HT1a and 5-HT2a receptors in attention and motor control: a mechanistic study in healthy volunteers , 2006, Psychopharmacology.

[24]  R. Dolan,et al.  Unconscious fear influences emotional awareness of faces and voices. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Olaf B. Paulson,et al.  MR-based automatic delineation of volumes of interest in human brain PET images using probability maps , 2005, NeuroImage.

[26]  O. Paulson,et al.  The effect of ketanserin on cerebral blood flow and cerebrovascular CO2 reactivity in healthy volunteers , 2005, Acta Neurochirurgica.

[27]  C. Svarer,et al.  Integrated software for the analysis of brain PET/SPECT studies with partial-volume-effect correction. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[28]  T. Dalgleish.  Basic Emotions , 2004 .

[29]  Morten L Kringelbach,et al.  Neural correlates of rapid reversal learning in a simple model of human social interaction , 2003, NeuroImage.

[30]  S. Rauch,et al.  Neurobiology of emotion perception II: implications for major psychiatric disorders , 2003, Biological Psychiatry.

[31]  Claus Svarer,et al.  Quantification of 5-HT2A Receptors in the Human Brain Using [18F]Altanserin-PET and the Bolus/Infusion Approach , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[32]  E. Rolls,et al.  Changes in emotion after circumscribed surgical lesions of the orbitofrontal and cingulate cortices. , 2003, Brain : a journal of neurology.

[33]  R Turner,et al.  Optimized EPI for fMRI studies of the orbitofrontal cortex , 2003, NeuroImage.

[34]  P. Cowen,et al.  Tryptophan depletion decreases the recognition of fear in female volunteers , 2003, Psychopharmacology.

[35]  H. Mayberg.  Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. , 2003, British medical bulletin.

[36]  R. Glennon,et al.  Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists. , 2002, Current topics in medicinal chemistry.

[37]  R. Adolphs.  Recognizing emotion from facial expressions: psychological and neurological mechanisms. , 2002, Behavioral and cognitive neuroscience reviews.

[38]  G H Glover,et al.  Image‐based method for retrospective correction of physiological motion effects in fMRI: RETROICOR , 2000, Magnetic resonance in medicine.

[39]  A. Damasio,et al.  Emotion, decision making and the orbitofrontal cortex. , 2000, Cerebral cortex.

[40]  P. Goldman-Rakic,et al.  Segregation of serotonin 5‐HT2A and 5‐HT3 receptors in inhibitory circuits of the primate cerebral cortex , 2000, The Journal of comparative neurology.

[41]  P S Goldman-Rakic,et al.  5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Karl J. Friston,et al.  Psychophysiological and Modulatory Interactions in Neuroimaging , 1997, NeuroImage.

[43]  E. Rolls,et al.  Face and voice expression identification in patients with emotional and behavioural changes following ventral frontal lobe damage , 1996, Neuropsychologia.

[44]  Jerry L Prince,et al.  Measurement of Radiotracer Concentration in Brain Gray Matter Using Positron Emission Tomography: MRI-Based Correction for Partial Volume Effects , 1992, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[45]  E. Boddeke,et al.  Characterization of flufylline, fluprofylline, ritanserin, butanserin and R 56413 with respect to in‐vivo α1‐, α2‐ and 5‐HT2‐receptor antagonism and in‐vitro affinity for α1‐, α2‐ and 5‐HT2‐receptors: comparison with ketanserin , 1986 .

[46]  W. Herrmann,et al.  Combined pharmaco-EEG and pharmacopsychological study to estimate CNS effects of ketanserin in hypertensive patients. , 1986, Neuropsychobiology.

[47]  E. Boddeke,et al.  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. , 1986, The Journal of pharmacy and pharmacology.

[48]  M. Lorr,et al.  Manual for the Profile of Mood States , 1971 .