Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD).
Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed.
We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030).
The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.
"This modulation of threat-related information processing is associated with increased stress and anxiety (Mekli et al., 2011). Furthermore, the density and binding potential of 5-HT1A receptors was significantly reduced in the prefrontal, amygdala, and temporal areas of the brain in patients with anxiety (Lanzenberger et al., 2007); these brain regions are strongly activated during emotional face processing (Dima et al., 2011). In line with these finding, 5-HT1A receptor agonist, such as buspirone, have been used as a treatment of general anxiety disorders (Lee et al., 2005) and as an augmentation of antidepressant drugs (Harvey and Balon, 1995). "
"The sample size can be considered as quite small; however, when reviewing the literature for imaging studies, our sample size of 17/19, for PET/ MRI respectively, seems appropriate and comparable with other investigations. Naturally, a power calculation was performed prior to the study on the basis of another PET study in anxiety disorder patients showing significant differences in 5-HT 1A bi nding when 12 patients and 18 healthy subjects were contrasted (Lanzenberger et al., 2007). Regarding the nonsignifi cant differences in the VBM analysis, it is possible that the low sample size impeded detection of subtle changes in gray matter volume . "
"PET studies revealed decreased 5- HT 1A heteroreceptor levels in the orbitofrontal, anterior cingulate, occipital, and parietal cortex in untreated or treated depressed patients, and it was also decreased in patients with remitted depressive episodes and unmedicated subjects (Bhagwagar et al. 2004; Drevets et al. 2000, 2007; Sargent et al. 2000). Furthermore, reduced 5-HT 1A heteroreceptor levels have also been reported in patients with social anxiety disorders (Lanzenberger et al. 2007), as well as in cortical regions from patients suffering from panic disorder (Nash et al. 2008; Neumeister et al. 2004), although not all studies are in agreement (see Meltzer et al. 2004; Parsey et al. 2006; Parsey 2010). Nevertheless, despite some discrepant findings, overall evidence suggests that 5-HT 1A receptor function is altered in clinical populations when compared to controls. "
[Show abstract][Hide abstract] ABSTRACT: Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in both disorders.
In this review, we examine the function of 5-HT1A receptor subpopulations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor versus heteroreceptor) and the temporal (developmental versus adult) roles of the endogenous 5-HT1A receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors.
It is difficult to unambiguously distinguish the effects of different populations of the 5-HT1A receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for the distinct roles of these populations in governing emotion-related behavior is emerging.
There is strong and growing evidence for a functional dissociation between auto- and heteroreceptor populations in mediating anxiety and depressive-like behaviors, respectively. Furthermore, while it is well established that 5-HT1A receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT1A heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects.
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