Cortical serotonin 5-HT(2A) receptor binding and social communication in adults with Asperger's syndrome: An in vivo SPECT study
ABSTRACT The cause of autistic spectrum disorder (i.e., autism and Asperger's syndrome) is unknown. The serotonergic (5-HT) system may be especially implicated. However, cortical 5-HT2A receptor density in adults with the disorder has not been examined, to the authors' knowledge.
The authors investigated cortical 5-HT2A receptor binding in eight adults with Asperger's syndrome and in 10 healthy comparison subjects with single photon emission computed tomography and the selective 5-HT2A receptor ligand 123I iodinated 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150).
People with Asperger's syndrome had a significant reduction in cortical 5-HT2A receptor binding in the total, anterior, and posterior cingulate; bilaterally in the frontal and superior temporal lobes; and in the left parietal lobe. Also, reduced receptor binding was significantly related to abnormal social communication.
The authors' findings suggest that adults with Asperger's syndrome have abnormalities in cortical 5-HT2A receptor density and that this deficit may underlie some clinical symptoms.
- SourceAvailable from: Eileen Daly
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- "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). Also, our finding that thalamic modulation by ATD is correlated with severity of RSRB in autism parallels findings by others of a correlation between repetitive behaviours and thalamic serotonin transporter binding (Nakamura et al., 2010). "
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
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- "According to recent animal models, during pregnancy embryonic 5-HT is initially produced by the placenta using maternal tryptophan, whereas subsequently 5-HT synthesis is undertaken by serotonergic neurons located in raphe nuclei and extending their projections to the cortex, basal ganglia, amygdala, hippocampus and hypothalamus (Bonnin et al., 2011). Abnormalities in brain 5-HT systems were also reported in ASD, including an altered developmental trajectory of 5-HT turnover (Chugani et al., 1999) and reduced binding of 5-HT receptors and SERT (Murphy et al., 2006; Nakamura et al., 2010). "
ABSTRACT: Elevated blood serotonin (5-HT) levels were the first biomarker identified in autism research. Many studies have contrasted blood 5-HT levels in autistic patients and controls, but different measurement protocols, technologies, and biomaterials have been used through the years. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and between-study heterogeneity, while verifying whether and to what extent different methodological approaches influence the strength of this association. Our literature search strategy identified 551 papers, from which 22 studies providing patient and control blood 5-HT values were selected for meta-analysis. Significantly higher 5-HT levels in autistic patients compared to controls were recorded both in whole blood (WB) [O.R.=4.6; (3.1–5.2); P=1.0×10−12], and in platelet-rich plasma (PRP) [O.R.=2.6 (1.8–3.9); P=2.7×10−7]. Predictably, studies measuring 5-HT levels in platelet-poor plasma (PPP) yielded no significant group difference [O.R.=0.54 (0.2–2-0); P=0.36]. Altogether, elevated 5-HT blood levels were recorded in 28.3% in WB and 22.5% in PRP samples of autistic individuals, as reported in 15 and 4 studies, respectively. Studies employing HPLC vs fluorometric assays yield similar cumulative effect sizes, but the former display much lower variability. In summary, despite some limitations mainly due to small study sample sizes, our results significantly reinforce the reliability of elevated 5-HT blood levels as a biomarker in ASD, providing practical indications potentially useful for its inclusion in multi-marker diagnostic panels for clinical use.European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2014; 24(6). DOI:10.1016/j.euroneuro.2014.02.004
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- "In ASD, however, 5-HT is thought to be the main abnormal neurotransmitter in the disorder, and there is a wealth of research supporting the presence of genetic and biochemical serotonergic abnormalities, leading to high levels of 5-HT (Piven et al. 1991; Chugani et al. 1997, 1999; Mulder et al. 2004; Murphy et al. 2006; Hranilovic et al. 2007; Makkonen et al. 2008; Zafeiriou et al. 2009; Nakamura et al. 2010), in addition to the positive effect of Fluoxetine on stereotyped behaviors (Fatemi et al. 1998; Hollander et al. 2005, 2012; Carrasco et al. 2012) and brain activation in areas related to reward reversal (Buchsbaum et al. 2001; Dichter et al. 2010) in children and adults with ASD. These differing biochemical abnormalities may have accounted for the positive upregulation effect of Fluoxetine on ASD mPFC activation and its negative downregulating effect on mPFC activation in ADHD. "
ABSTRACT: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) share brain function abnormalities during cognitive flexibility. Serotonin is involved in both disorders, and selective serotonin reuptake inhibitors (SSRIs) can modulate cognitive flexibility and improve behavior in both disorders. Thus, this study investigates shared and disorder-specific brain dysfunctions in these 2 disorders during reward reversal, and the acute effects of an SSRI on these. Age-matched boys with ADHD (15), ASD (18), and controls (21) were compared with functional magnetic resonance imaging (fMRI) during a reversal task. Patients were scanned twice, under either an acute dose of Fluoxetine or placebo in a double-blind, placebo-controlled randomized design. Repeated-measures analyses within patients assessed drug effects. Patients under each drug condition were compared with controls to assess normalization effects. fMRI data showed that, under placebo, ASD boys underactivated medial prefrontal cortex (mPFC), compared with control and ADHD boys. Both patient groups shared decreased precuneus activation. Under Fluoxetine, mPFC activation was up-regulated and normalized in ASD boys relative to controls, but down-regulated in ADHD boys relative to placebo, which was concomitant with worse task performance in ADHD. Fluoxetine therefore has inverse effects on mPFC activation in ASD and ADHD during reversal learning, suggesting dissociated underlying serotonin abnormalities.Cerebral Cortex 01/2014; 25(7). DOI:10.1093/cercor/bht365