An Association Between Serotonin 1A Receptor, Gray Matter Volume, and Sociability in Healthy Subjects and in Autism Spectrum Disorder.

Central serotonin is an important molecular pathway, involved in the regulation of social behavior and gray matter volume (GMV). In men with autism spectrum disorders (ASD), the serotonergic system and the GMV have been found disrupted. Here, we investigated the relation between serotonin, GMV, and social personality in men with typical development (TD) and in men with ASD. We combined anatomical magnetic resonance imaging, Positron emission tomography scan with 2'-methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine radioligand and revised NEO personality inventory personality questionnaire to examine the association between serotonin 1A receptor (5-HT1A R) binding potential, GMV and social personality in 24 adult male TD subjects and 18 male men with ASD. In both groups, we found a positive correlation between 5-HT1A R binding potential and GMV in a region dependent manner. In the TD group, we observed a negative correlation between 5-HT1A R and GMV in the left and right posterior putamen. 5HT1A R binding and GMV in the putamen further correlated with social personality scores in the TD group. None of these associations were found in men with ASD, although no differences were observed for 5-HT1A R concentration among the two groups. Our findings point to a deregulation of 5-HT1A R density in the striatum of men with ASD, a failure that might contribute to their social disturbances. Serotonin is suspected to be involved in the pathophysiology of autism. We provide evidence for a role of serotonin 1A receptor in social behavior through a specific regulation of GMV in the putamen region in neurotypical subjects but not in men with autism. This suggests a potential impairment of the serotonergic system in men with autism which may contribute to patients' social disturbances. Our findings suggest further investigation on the role of serotonin 1A receptor and its activity in the striatum to regulate social behavior. Autism Res 2020, 13: 1843-1855. © 2020 International Society for Autism Research and Wiley Periodicals LLC LAY SUMMARY: Serotonin is suspected to be involved in the pathophysiology of autism. We provide evidence for a role of serotonin 1A receptor in social behavior through a specific regulation of gray matter volume in the putamen region in neurotypical subjects but not in men with autism. This suggests a potential impairment of the serotonergic system in men with autism which may contribute to patients' social disturbances. Our findings suggest further investigation on the role of serotonin 1A receptor and its activity in the striatum to regulate social behavior.

Oxytocin Fails to Recruit Serotonergic Neurotransmission in the Autistic Brain.

Oxytocin (OT), a neuropeptide involved in affiliation has been shown to enhance social skills in patients with autism spectrum disorders (ASD). Nevertheless, OT improvements seem ephemeral. Animal research has demonstrated OT action on serotonin (5-HT), an interaction that we also found in the healthy human brain. Whether such synaptic interplay also occurs in ASD patients is unknown. To address this issue, we mapped the effects of intranasal OT on 5-HT in 18 patients with ASD and 24 healthy controls (HC) in a double blind, placebo controlled, within subject PET-scan experiment. Each participant underwent two scans: baseline and spray (OT or placebo). Using the radiotracer [18 F]MPPF, marking the 5-HT 1A receptor (5-HT1AR), we measured MPPF-Binding Potential (BP) as an index of OT-induced serotonin functional modulation. At baseline ASD patients did not differ from controls for 5-HT1AR concentration and distribution. However, while OT significantly increased MPPF BP in several brain regions of HC, no changes were observed in the ASD group. Serotonin serum concentration analysis corroborated these results. Our findings suggest a disturbed OT-serotonin interaction in autism. This may limit the potential benefits of OT in these patients and open the ways to investigate combined OT-serotonin treatments.

A comparison of methods to measure central and peripheral oxytocin concentrations in human and non-human primates.

Oxytocin (OT) concentration in the blood is considered to be a marker of its action in the brain. However, two problems have emerged when measuring OT level in the blood. First, it is unclear whether different methods of assessment lead to similar OT values. Second, it is unclear if plasma OT concentrations is informative on what OT does in the brain. To clarify these issues, we collected cerebrospinal fluid (CSF) from the brain ventricle of 25 patients during surgery to compare with plasma OT after simultaneous blood withdrawal. Additionally, we collected 12 CSF and blood samples from non-human primates while awake or under anaesthesia. We used four methods to assay OT concentrations: Commercial EIA with/without extraction, laboratory developed EIA with filtration and RIA with extraction. Three of these methods showed a positive correlation between plasma and CSF OT, suggesting a link between plasma and central OT, at least under specific testing conditions. However, none of the methods correlated to each other. Our results show major disagreements among methods used here to measure peripheral and brain OT and therefore they call for more caution when plasma OT is taken as a marker of central OT.

Switching brain serotonin with oxytocin.

Serotonin (5-HT) and oxytocin (OXT) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism. We asked whether these chemical messengers interact in the regulation of emotion-based behavior by administering OXT or placebo to 24 healthy subjects and mapping cerebral 5-HT system by using 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine ([(18)F]MPPF), an antagonist of 5-HT1A receptors. OXT increased [(18)F]MPPF nondisplaceable binding potential (BPND) in the dorsal raphe nucleus (DRN), the core area of 5-HT synthesis, and in the amygdala/hippocampal complex, insula, and orbitofrontal cortex. Importantly, the amygdala appears central in the regulation of 5-HT by OXT: [(18)F]MPPF BPND changes in the DRN correlated with changes in right amygdala, which were in turn correlated with changes in hippocampus, insula, subgenual, and orbitofrontal cortex, a circuit implicated in the control of stress, mood, and social behaviors. OXT administration is known to inhibit amygdala activity and results in a decrease of anxiety, whereas high amygdala activity and 5-HT dysregulation have been associated with increased anxiety. The present study reveals a previously unidentified form of interaction between these two systems in the human brain, i.e., the role of OXT in the inhibitory regulation of 5-HT signaling, which could lead to novel therapeutic strategies for mental disorders.

Oxytocin's fingerprint in personality traits and regional brain volume.

Oxytocin has a fundamental role in social behavior. In humans, supporting evidence shows that oxytocin enhances people's ability to trust or affiliate with others. A key question is whether differences in plasma oxytocin concentration in humans are related to people's differences in their social traits of personality and if such differences are reflected in the structural organization of brain areas responsive to the action of this hormone. We examined the correlation between oxytocin plasma levels and personality traits in 30 healthy subjects, tested with the Inventory revised neuroticism-extroversion-openness personality inventory (NEO-PI-R). By using the voxel-based morphometry technique, we also investigated changes in gray matter volume as a function of the plasma oxytocin level and NEO-PI-R scores. A positive correlation was found between plasma oxytocin and extraversion scores, a dimension that captures social affiliative tendencies. Moreover, we found an inverse correlation between plasma oxytocin and the volume of the right amygdala and the right hippocampus, 2 brain areas implicated in fear and anxiety. Finally, we showed that the amygdala-hippocampal complex correlate negatively with extraversion scores. Our findings provide evidence for a neural mechanism linking physiological oxytocin's variability and structural variation of brain regions relevant for emotion regulation to individual differences in affiliative personality traits.