Inhibition of serotonin transport by (+)McN5652 is noncompetitive

Hummerich, René; Schulze, Oliver; Rädler, T.; Mikecz, Pál; Reimold, Matthias; Brenner, Winfried; Clausen, M.; Schloss, Patrick D.; Buchert, Ralph

doi:10.1016/j.nucmedbio.2005.12.009

Cited by 7 publications

(4 citation statements)

References 36 publications

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“…As f p is not measurable for the [ 11 C]McN 5652 radioligand, we cannot exclude the possibility of differences in f p between groups. The results reported here cannot be explained by differences in intrasynaptic 5-HT concentrations, as the [ 11 C]McN 5652 radioligand does not appear to be sensitive to endogenous neurotransmitter levels (Hummerich et al, 2006). …”

Section: Discussionmentioning

confidence: 71%

Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorder

Miller

Kinnally

Ogden

et al. 2009

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103

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Background Physical or psychological adversity in childhood is associated with a higher risk for depression in adulthood, and with persistent serotonergic abnormalities in humans and in animal models. We hypothesized that reported childhood abuse would be associated with lower brain serotonin transporter (5-HTT) binding potential (BPP, proportional to the number of available transporters) in adults. We examined healthy volunteers and subjects with major depressive disorder, a sample enriched for childhood abuse. Methods Regional brain 5-HTT BPP was measured using positron emission tomography with [11C]McN 5652 and a metabolite corrected arterial input function in 43 healthy volunteers and 23 subjects in a major depressive episode, ten of whom reported a history of sexual and/or physical abuse before age 15, and 13 of whom did not. As only two healthy volunteers reported childhood abuse, primary analyses were restricted to the depressed sample, with healthy controls presented as comparators. Results Depressed subjects reporting childhood abuse had lower 5-HTT BPP than non-abused depressed subjects across all brain regions examined (p=0.017). The groups did not differ in relevant demographic or clinical variables. Genotype frequencies of a functional polymorphism in the 5-HTT gene promoter (5-HTTLPR) did not differ between the groups. Conclusions Reported childhood abuse is associated with lower 5-HTT BPP in this sample of subjects with major depression, consistent with other reports that childhood adversity can lower serotonergic function permanently. Lower 5-HTT BPP may represent a biological pathway through which early life stress predisposes to the development of subsequent psychiatric illness, including major depressive disorder.

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Section: Discussionmentioning

confidence: 71%

Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorder

Miller

Kinnally

Ogden

et al. 2009

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103

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“…This is an especially important consideration in our attempts to study 5-HT, as a radiotracer of equivalent value as [ 11 C]raclopride has been to dopamine has not yet been identified (for review see Paterson et al, 2010 (Paterson et al 2010)). For example, [ 11 C]McN5652 BP ND presumably reflects 5-HTT density and/or affinity because[ 11 C]McN5652 is not displaced from 5-HTT sites by physiologically relevant 5-HT concentrations (Hummerich et al 2006, Meyer 2007). Therefore, [ 11 C]McN5652 BP ND appears to remain relatively unaffected by endogenous 5-HT (Hummerich et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…For example, [ 11 C]McN5652 BP ND presumably reflects 5-HTT density and/or affinity because[ 11 C]McN5652 is not displaced from 5-HTT sites by physiologically relevant 5-HT concentrations (Hummerich et al 2006, Meyer 2007). Therefore, [ 11 C]McN5652 BP ND appears to remain relatively unaffected by endogenous 5-HT (Hummerich et al 2006). One model, as suggested by Meyer et al (Meyer 2007), proposes a clearance effect of 5-HTT, with less functioning 5-HTT associated with greater extracellular 5-HT.…”

Section: Discussionmentioning

confidence: 99%

Interaction between serotonin transporter and dopamine D2/D3 receptor radioligand measures is associated with harm avoidant symptoms in anorexia and bulimia nervosa

Bailer

Frank

Price

et al. 2013

Psychiatry Research: Neuroimaging

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Rationale Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) have alterations of measures of serotonin (5-HT) and dopamine (DA) function, which persist after long-term recovery and are associated with elevated harm avoidance (HA), a measure of anxiety and behavioral inhibition. Objective Based on theories that 5-HT is an aversive motivational system that may oppose a DA-related appetitive system, we explored interactions of positron emission tomography (PET) radioligand measures that reflect portions of these systems. Methods Twenty-seven individuals recovered (REC) from eating disorders (EDs) (7 AN-BN, 11 AN, 9 BN) and 9 control women (CW) were analyzed for correlations between [11C]McN5652 and [11C]raclopride binding. Results There was a positive correlation between [11C]McN5652 binding potential BPnon displaceable(ND)) and [11C]raclopride BPND for the dorsal caudate (r(27) = .62; p < .001), antero-ventral striatum (r(27) = .55, p = .003), middle caudate (r(27) = .68; p < .001), ventral (r(27) = .64; p < .001) and dorsal putamen (r(27) = .42; p = .03). No significant correlations were found in CW. [11C]raclopride BPND, but not [11C]McN5652 BPND, was significantly related to HA in REC EDs. A linear regression analysis showed that the interaction between [11C]McN5652 BPND and [11C]raclopride BPND in the dorsal putamen significantly (b = 140.04; t (22) = 2.21; p = .04) predicted HA. Conclusions This is the first study using PET and the radioligands [11C]McN5652 and [11C]raclopride to show a direct relationship between 5-HT transporter and striatal DA D2/D3 receptor binding in humans, supporting the possibility that 5-HT and DA interactions contribute to HA behaviors in EDs.

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“…9,13,14 As a result, b-CIT binding to 5-HTT can be assessed only in brain areas where dopamine transporters are rare and where the radioligand is displaced exclusively by selective serotonin reuptake inhibitors. 3,9,10,15 Using [ 11 C]McN, a positron emission tomography (PET) ligand with selective affinity for 5-HTT that is assumed to be not displaceable by endogenous serotonin, 16 Parsey et al 17 observed reduced midbrain and amygdala 5-HTT availability in a group of 25 patients with major depression, while Ichimiya et al 18 reported unaltered [ 11 C]McN binding in the midbrain and increased binding in the thalamus in 7 patients with major depression. The 5-HTT ligand [ 11 C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) is reported to have a better signal-to-noise ratio than [ 11 C]McN, 19 also binds selectively to 5-HTT 20 and is also assumed to measure 5-HTT availability independent from synaptic levels of endogenous serotonin.…”

Section: Introductionmentioning

confidence: 99%

Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study

et al. 2008

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Serotonergic dysfunction may contribute to negative mood states in affective disorders. Some in vivo imaging studies showed reduced availability of serotonin transporters (5-HTT) in the brainstem and thalamus of patients with major depression. We tested the hypothesis that 5-HTT availability is reduced in unmedicated unipolar patients with major depression compared to healthy control subjects matched for gender, age, genotype and smoking status. Availability of 5-HTT was measured in vivo with positron emission tomography and [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) in the midbrain, thalamus and amygdala. DASB binding was correlated with the severity of depression (Beck's Depression Inventory), anxiety (Spielberger's State-Trait Anxiety Inventory) and personality traits (Temperament and Character Inventory). Patients with major depression displayed reduced 5-HTT availability in the thalamus (P=0.005). In patients, low serotonin transporter availability correlated with high anxiety (thalamus: r=-0.78, P=0.004; midbrain: r=-0.78, P=0.004; amygdala: r=-0.80, P=0.003). Correlations with severity of depression were weaker and did not survive correction for multiple testing. These results support the hypothesis that central serotonergic dysfunction is associated with negative mood states in affective disorders. In the thalamus, a low serotonin reuptake capacity may interfere with thalamic control of cortical excitability and contribute to anxiety rather than depression per se in major depression.

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Inhibition of serotonin transport by (+)McN5652 is noncompetitive

Cited by 7 publications

References 36 publications

Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorder

Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorder

Interaction between serotonin transporter and dopamine D2/D3 receptor radioligand measures is associated with harm avoidant symptoms in anorexia and bulimia nervosa

Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study

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