Varnäs K, Halldin C, Hall H. Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum Brain Mapp 22: 246-260
ABSTRACT Several neurochemical in vitro and in vivo imaging studies have been aimed at characterizing the localization of serotonin receptors and transporters in the human brain. In this study, a detailed comparison of the distribution of a number of 5-HT receptor subtypes and the 5-HT transporter was carried out in vitro using human postmortem brain tissue. Anatomically adjacent whole hemisphere sections were incubated with specific radioligands for the 5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(4) receptors and the 5-HT transporter. The autoradiograms revealed different laminar and regional distribution patterns in the isocortex, where 5-HT(1A) and 5-HT(4) receptor binding showed highest densities in superficial layers and 5-HT(2A) receptor binding was most abundant in middle layers. In cortical regions, 5-HT transporters were concentrated to several limbic lobe structures (posterior uncus, entorhinal, cingulate, insular and temporal polar regions). 5-HT(1A) receptor densities were also high in limbic cortical regions (hippocampus, posterior entorhinal cortex, and subcallosal area) compared to the isocortex. Subregionally different distribution patterns were observed in the basal ganglia with a trend toward higher levels in ventral striatal (5-HT(1B) receptors) and pallidal (5-HT transporters and 5-HT(1B) receptors) regions. The localization in regions belonging to limbic cortico-striato-pallido-thalamic circuits is in line with the documented role of 5-HT in modulation of mood and emotion, and the suggested involvement of this system in pathophysiology of various psychiatric disorders. The qualitative and quantitative information reported in this study might provide important complements to in vivo neuroimaging studies of the 5-HT system.
- SourceAvailable from: Markus Mitterhauser
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- "particularly useful for voxel-wise analyses. Here, the clearance rate of the radiotracer from the reference region to plasma (k 2 ') was calculated from the insula (receptor-rich region) and cerebellar gray matter (receptor-poor region) (Ichise et al., 2003; Varnas et al., 2004) using the simplified reference tissue model 2 (Wu and Carson, 2002). These regions of interest were taken from an automated anatomical labeling-based atlas (Tzourio-Mazoyer et al., 2002; Savli et al., 2012), whereas the cerebellar gray matter (excluding vermis and sagittal sinus) served as reference region because of negligible specific receptor binding in this area as previously described (Hall et al., 1997; Hahn et al., 2010). "
ABSTRACT: Recently, Silexan, a patented active substance comprised of an essential oil produced from Lavandula angustifolia flowers, has been authorized in Germany as a medicinal product for the treatment of states of restlessness related to anxious mood. Its efficacy has been shown in several forms of anxiety disorders. Findings from preclinical and clinical studies attribute a major role in the pathogenesis and treatment of anxiety to the serotonin-1A receptor (5-HT1A). To elucidate the effect of Silexan on 5-HT1A receptor binding, 17 healthy men underwent two positron emission tomography measurements using the radioligand [carbonyl-(11)C]WAY-100635 following the daily intake of 160 mg Silexan or placebo over a minimum of eight weeks, respectively (randomized, double-blind, cross-over design). Additionally, structural magnetic resonance imaging and voxel-based morphometry analysis was performed to determine potential effects on gray matter microstructure. 5-HT1A receptor binding potential was shown to be significantly reduced following the intake of Silexan compared to placebo in two large clusters encompassing the temporal gyrus, the fusiform gyrus, the hippocampus on one hand as well as the insula and the anterior cingulate cortex on the other hand. No effects of Silexan on gray matter volume could be detected in this investigation. This PET study proposes an involvement of the serotonin-1A receptor in the anxiolytic effects of Silexan. © The Author 2014. Published by Oxford University Press on behalf of CINP.The International Journal of Neuropsychopharmacology 10/2014; 18(4). DOI:10.1093/ijnp/pyu063 · 4.01 Impact Factor
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- "Accordingly, emotion-related brain regions show sexual dimorphism regarding their neural development (Suzuki et al. 2005; Tottenham and Sheridan 2010). Importantly, the amygdala, the hippocampus, and the prefrontal cortex are involved in processing psychological stress (Herman et al. 1996; Herman and Cullinan 1997), and additionally, exhibit a high density of glucocorticoid (Teicher et al. 2003) and serotonin receptors (Molodtsova and Il'iuchenok 1990; Varnas et al. 2004; Berumen et al. 2012). This corresponds well with our results, indicating that these areas were neural targets of the interactive effect between MAOA, CLS, and sex. "
ABSTRACT: Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) genotype, environmental adversity, and sex in the pathophysiology of aggression. The present study aimed to clarify the impact of this interaction on neural activity in aggression-related brain systems. Functional magnetic resonance imaging was performed in 125 healthy adults from a high-risk community sample followed since birth. DNA was genotyped for the MAOA-VNTR (variable number of tandem repeats). Exposure to childhood life stress (CLS) between the ages of 4 and 11 years was assessed using a standardized parent interview, aggression by the Youth/Young Adult Self-Report between the ages of 15 and 25 years, and the VIRA-R (Vragenlijst Instrumentele En Reactieve Agressie) at the age of 15 years. Significant interactions were obtained between MAOA genotype, CLS, and sex relating to amygdala, hippocampus, and anterior cingulate cortex (ACC) response, respectively. Activity in the amygdala and hippocampus during emotional face-matching increased with the level of CLS in male MAOA-L, while decreasing in male MAOA-H, with the reverse pattern present in females. Findings in the opposite direction in the ACC during a flanker NoGo task suggested that increased emotional activity coincided with decreased inhibitory control. Moreover, increasing amygdala activity was associated with higher Y(A)SR aggression in male MAOA-L and female MAOA-H carriers. Likewise, a significant association between amygdala activity and reactive aggression was detected in female MAOA-H carriers. The results point to a moderating role of sex in the MAOA× CLS interaction for intermediate phenotypes of emotional and inhibitory processing, suggesting a possible mechanism in conferring susceptibility to violence-related disorders.Cerebral Cortex 10/2014; DOI:10.1093/cercor/bhu249 · 8.67 Impact Factor
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- "Our results also add to existing evidence that serotonin may play a key role in the pathophysiology of autism. The brain areas that we found to be differentially modulated by ATD form part of a fronto-striato-thalamo-cerebellar network of inhibitory control that develops progressively with age (Rubia et al., 2007), and has intermediate-to-high levels of serotonin receptors and transporters (Pazos et al., 1987; Varnä s et al., 2004) in healthy populations. Further, it has previously been reported by ourselves and others that in these regions, subjects with ASD have significant differences from controls in serotonin synthesis (Chugani et al., 1997), transporters (Nakamura et al., 2010) and 2A receptors (Murphy et al., 2006). "
ABSTRACT: It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target.Brain 07/2014; 137(9). DOI:10.1093/brain/awu178 · 9.20 Impact Factor