5-HT 1a receptors in anxiety disorders

Background: Based on animal and human clinical studies, there is circumstantial evidence that the neurotransmitter serotonin (5-HT), by binding to 5-HT1A receptors, plays a key role in modulating anxiety. The partial 5-HT1a receptor agonists buspirone had modest antianxiety effects. Using [carbonyl-11C]WAY-100635 and positron emission tomography (PET), 5-HT1A receptors can be investigated in humans. Tauscher et al. recently presented in a pilot PET study, which was conducted at the PET Centre of the Centre for Addiction and Mental Health, University of Toronto, Canada, an inverse relationship between cortical 5-HT1A receptor binding potential and trait anxiety, as assessed by the self-report version of the revised NEO Personality Inventory. Aim of the study: We aim at investigating the 5-HT1a binding potential (BP) in different cerebral regions of interest by means of PET and the selective 5-HT1a antagonist ligand [carbonyl-11C]WAY-100635 in patients suffering from an anxiety disorder, in particular with DSM-IV diagnosis of panic disorder (PD), social phobia or generalized anxiety disorder (GAD). Based on the above mentioned animal models and on a pilot study in healthy volunteers, we hypothesize to find a lower 5-HT1a receptor binding potential in anxiety disorder patients in comparison to an healthy control group. Additionally the binding potential will be investigated in patients after successful psychopharmacological treatment of the anxiety disorder with an SSRI in state of total remission. Materials and Methods: A DSM-IV diagnosis of PD, social phobia or GAD will be established by a structured clinical interview for DSM-IV (SCID). Patients and volunteers will have one [11C]WAY-100635 PET scan and one magnetic resonance imaging (MRI) scan, which will be co-registered to the PET scan for regional quantitative analysis of 5-HT1A receptor binding. A second group of patients will be treated psychopharmacologically and a PET scan will be performed at the timepoint of remission of the anxiety disorder. Results obtained in patients will be compared to a healthy control group by means of two approaches: a region-of-interest (ROI)-based analysis using ROI delineated on the co-registered MRI based on anatomical landmarks, and a voxel-wise analysis using statistical parameter mapping with SPM99.

The neurotransmitter serotonin plays a key role in the regulation of affective states. Drugs modulating the serotonergic system are widely used in the treatment of depression and anxiety disorders. Recent studies in humans and nonhuman primates suggested a central role of the main inhibitory serotonergic receptor subtype, the serotonin-1A receptor, in modulating anxiety. In addition, mice lacking the serotonin-1A receptor are showing increased anxious behaviour. Here we used positron emission tomography (PET) and the radioligand [carbonyl-11C]WAY-100635 to investigate the serotonin-1A receptor binding in patients suffering from social anxiety disorder (social phobia) compared to a healthy control group. We found a significantly lower serotonin-1A receptor binding potential in several brain areas of patients. This reduction was most pronounced in limbic brain areas involved in the regulation of emotions and affective states. There was also a significant reduction in the raphe nuclei, a brain area regulating serotonergic activity. The main finding of this study is a reduction in binding of the main inhibitory serotonergic receptor subtype in anxiety patients. The results indicate an altered serotonergic neurotransmission in social anxiety disorder and emphasize the central role of the amygdala and frontal brain areas in the modulation of anxious states. These results are consistent to the reduction of serotonin-1A receptor binding in panic disorder and anxious healthy subjects. Therefore, the serotonin-1A receptor might be a promising target for the development of drugs used in the treatment of human anxiety disorders. Further details of this study were published in: Lanzenberger et al., Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry. 2007 May 1;61(9):1081-9. Epub 2006 Sep 18.