Dopamine type-1 receptor binding in major depressive disorder assessed using positron emission tomography and [11c]nnc-112

The dopamine type-1 receptor has been implicated in major depressive disorder (MDD) by clinical and preclinical evidence from neuroimaging, post mortem, and behavioral studies. To date, however, selective in vivo assessment of D-1 receptors has been limited to the striatum in MDD samples manifesting anger attacks. We employed the PET radioligand, [C-11] NNC-112, to selectively assess D-1 receptor binding in extrastriatal and striatal regions in a more generalized sample of MDD subjects. The [C-11] NNC-112 nondisplaceable binding potential (BPND) was assessed using PET in 18 unmedicated, currently depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest analysis. The mean v receptor BPND was reduced (14%) in the left middle caudate of the MDD group relative to control group (p<0.05). Among the MDD subjects D-1 receptor BPND in this region correlated negatively with illness duration (r = -0.53; p = 0.02), and the left-to-right BPND ratio correlated inversely with anhedonia ratings (r = -0.65, p = 0.0040). The D-1 receptor BPND was strongly lateralized in striatal regions (p<0.002 for main effects of hemisphere in accumbens area, putamen, and caudate). In post hoc analyses, a group-by-hemisphere-by-gender interaction was detected in the dorsal putamen, which was accounted for by a loss of the normal asymmetry in depressed women (F = 7.33, p = 0.01). These data extended a previous finding of decreased striatal D-1 receptor binding in an MDD sample manifesting anger attacks to a sample selected more generally according to MDD criteria. Our data also more specifically localized this abnormality in MDD to the left middle caudate, which is the target of afferent neural projections from the orbitofrontal and anterior cingulate cortices where neuropathological changes have been reported in MDD. Finally, D-1 receptor binding was asymmetrical across hemispheres in healthy humans, compatible with evidence that dopaminergic function in the striatum is lateralized during reward processing, voluntary movement, and self-stimulation behavior

Genetic variation in htr2a influences serotonin transporter binding potential as measured using pet and [11c]dasb

In a previous study we showed that genetic variation in HTR2A, which encodes the serotonin 2A receptor, influenced outcome of citalopram treatment in patients with major depressive disorder. Since chronic administration of citalopram, which selectively and potently inhibits the serotonin transporter (5-HTT), putatively enhances serotonergic transmission, it is conceivable that genetic variation within HTR2A also influences pretreatment 5-HTT function or serotonergic transmission. The present study used positron emission tomography (PET) and the selective 5-HTT ligand, [C-11]DASB, to investigate whether the HTR2A marker alleles that predict treatment outcome also predict differences in 5-HTT binding. Brain levels of 5-HTT were assessed in vivo using PET measures of the non-displaceable component of the [C-11]DASB binding potential (BPND). DNA from 43 patients and healthy volunteers, all unmedicated, was genotyped with 14 single nucleotide polymorphisms located within or around HTR2A. Allelic association with BPND was assessed in eight brain regions, with covariates to control for race and ethnicity. We detected allelic association between [(11)]DASB BPND in thalamus and three markers in a region spanning the 3' untranslated region and second intron of HTR2A (rs7333412, p=0.000045; rs7997012, p=0.000086; rs977003, p=0.000069). The association signal at rs7333412 remained significant (p<0.05) after applying corrections for multiple testing via permutation. Genetic variation in HTR2A that was previously associated with citalopram treatment outcome was also associated with thalamic 5-HTT binding. While further work is needed to identify the actual functional genetic variants involved, these results suggest that a relationship exists between genetic variation in HTR2A and either 5-HTT expression or central serotonergic transmission that influences the therapeutic response to 5-HTT inhibition in major depression

Genetic variation in htr2a influences serotonin transporter binding potential as measured using pet and [11c]dasb

In a previous study we showed that genetic variation in HTR2A, which encodes the serotonin 2A receptor, influenced outcome of citalopram treatment in patients with major depressive disorder. Since chronic administration of citalopram, which selectively and potently inhibits the serotonin transporter (5-HTT), putatively enhances serotonergic transmission, it is conceivable that genetic variation within HTR2A also influences pretreatment 5-HTT function or serotonergic transmission. The present study used positron emission tomography (PET) and the selective 5-HTT ligand, [C-11]DASB, to investigate whether the HTR2A marker alleles that predict treatment outcome also predict differences in 5-HTT binding. Brain levels of 5-HTT were assessed in vivo using PET measures of the non-displaceable component of the [C-11]DASB binding potential (BPND). DNA from 43 patients and healthy volunteers, all unmedicated, was genotyped with 14 single nucleotide polymorphisms located within or around HTR2A. Allelic association with BPND was assessed in eight brain regions, with covariates to control for race and ethnicity. We detected allelic association between [(11)]DASB BPND in thalamus and three markers in a region spanning the 3\u27 untranslated region and second intron of HTR2A (rs7333412, p=0.000045; rs7997012, p=0.000086; rs977003, p=0.000069). The association signal at rs7333412 remained significant (p<0.05) after applying corrections for multiple testing via permutation. Genetic variation in HTR2A that was previously associated with citalopram treatment outcome was also associated with thalamic 5-HTT binding. While further work is needed to identify the actual functional genetic variants involved, these results suggest that a relationship exists between genetic variation in HTR2A and either 5-HTT expression or central serotonergic transmission that influences the therapeutic response to 5-HTT inhibition in major depression

Genetic variation in cholinergic muscarinic-2 receptor gene modulates m2 receptor binding in vivo and accounts for reduced binding in bipolar disorder

Genetic variation in the cholinergic muscarinic-2 (M-2) receptor gene (CHRM2) has been associated with the risk for developing depression. We previously reported that M-2-receptor distribution volume (V-T) was reduced in depressed subjects with bipolar disorder (BD) relative to depressed subjects with major depressive disorder (MDD) and healthy controls (HCs). In this study, we investigated the effects of six single-nucleotide polymorphisms (SNPs) for CHRM2 on M-2-receptor binding to test the hypotheses that genetic variation in CHRM2 influences M-2-receptor binding and that a CHRM2 polymorphism underlies the deficits in M-2-receptor V-T observed in BD. The M-2-receptor V-T was measured using positron emission tomography and [F-18]FP-TZTP in unmedicated, depressed subjects with BD (n = 16) or MDD (n = 24) and HCs (n = 25), and the effect of genotype on V-T was assessed. In the controls, one SNP (with identifier rs324650, in which the ancestral allele adenine (A) is replaced with one or two copies of thymine (T), showed a significant allelic effect on V-T in the pregenual and subgenual anterior cingulate cortices in the direction AA < AT < TT. In contrast, in BD subjects with the TT genotype, V-T was significantly lower than in BD subjects with the AT genotype in these regions. The BD subjects homozygous for the T -allele also showed markedly lower V-T (by 27 to 37% across regions) than HCs of the same genotype. Post hoc analyses suggested that T homozygosity was associated with a more severe illness course, as manifested by lower socioeconomic function, poorer spatial recognition memory and a greater likelihood of having attempted suicide. These data represent novel preliminary evidence that reduced M-2-receptor V-T in BD is associated with genetic variation within CHRM2. The differential impact of the M-2-receptor polymorphism at rs324650 in the BD and HC samples suggests interactive effects with an unidentified vulnerability factor for BD. Molecular Psychiatry (2011) 16, 407-418; doi:10.1038/mp.2010.24; published online 30 March 201

Dopamine type-1 receptor binding in major depressive disorder assessed using positron emission tomography and [11c]nnc-112

The dopamine type-1 receptor has been implicated in major depressive disorder (MDD) by clinical and preclinical evidence from neuroimaging, post mortem, and behavioral studies. To date, however, selective in vivo assessment of D-1 receptors has been limited to the striatum in MDD samples manifesting anger attacks. We employed the PET radioligand, [C-11] NNC-112, to selectively assess D-1 receptor binding in extrastriatal and striatal regions in a more generalized sample of MDD subjects. The [C-11] NNC-112 nondisplaceable binding potential (BPND) was assessed using PET in 18 unmedicated, currently depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest analysis. The mean v receptor BPND was reduced (14%) in the left middle caudate of the MDD group relative to control group (p<0.05). Among the MDD subjects D-1 receptor BPND in this region correlated negatively with illness duration (r = -0.53; p = 0.02), and the left-to-right BPND ratio correlated inversely with anhedonia ratings (r = -0.65, p = 0.0040). The D-1 receptor BPND was strongly lateralized in striatal regions (p<0.002 for main effects of hemisphere in accumbens area, putamen, and caudate). In post hoc analyses, a group-by-hemisphere-by-gender interaction was detected in the dorsal putamen, which was accounted for by a loss of the normal asymmetry in depressed women (F = 7.33, p = 0.01). These data extended a previous finding of decreased striatal D-1 receptor binding in an MDD sample manifesting anger attacks to a sample selected more generally according to MDD criteria. Our data also more specifically localized this abnormality in MDD to the left middle caudate, which is the target of afferent neural projections from the orbitofrontal and anterior cingulate cortices where neuropathological changes have been reported in MDD. Finally, D-1 receptor binding was asymmetrical across hemispheres in healthy humans, compatible with evidence that dopaminergic function in the striatum is lateralized during reward processing, voluntary movement, and self-stimulation behavior