Brain dopamine D-1 receptors in twins discordant for schizophrenia
ABSTRACT It has been suggested that deficits in higher-order cognitive functions serve as intermediate phenotypic indicators of genetic vulnerability to schizophrenia. The dopamine hypothesis of schizophrenia postulates that insufficiency of dopamine transmission in the prefrontal cortex contributes to the cognitive deficits observed in patients with the disease, and there is robust empirical evidence for a central role of prefrontal cortex dopamine D(1) receptors in working memory functions.
The authors examined the genetic and nongenetic effects on D(1) receptor binding in schizophrenia by studying monozygotic and dizygotic twin pairs discordant for schizophrenia as well as healthy comparison twins using positron emission tomography (PET) and the D(1) receptor antagonist ligand [(11)C]SCH 23390. Performance on neuropsychological tests sensitive to frontal lobe functioning was evaluated.
High D(1) receptor density in the medial prefrontal cortex, superior temporal gyrus, and heteromodal association cortex (angular gyrus) was associated with increasing genetic risk for schizophrenia (comparison twins < unaffected dizygotic co-twins < unaffected monozygotic co-twins). Medicated schizophrenia patients demonstrated a widespread reduction in D(1) receptor binding when compared with the unaffected co-twin, and higher doses of antipsychotics were associated with lower D(1) receptor binding in the frontotemporal regions.
This study demonstrated an association between genetic risk for schizophrenia and alterations in cortical D(1) receptor binding, an observation that has implications for future studies of the molecular genetics of schizophrenia. In addition, the data indicate a widespread reduction of D(1) receptor binding in medicated schizophrenia patients, supporting a link between antipsychotic drug action and dopamine D(1) receptor down-regulation.
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ABSTRACT: The catechol-O-methyltransferase (COMT) gene is a schizophrenia susceptibility gene. A common functional polymorphism of this gene, Val158/158Met, has been proposed to influence gray matter volume (GMV). However, the effects of this polymorphism on cortical thickness/surface area in schizophrenic patients are less clear. In this study, we explored the relationship between the Val158Met polymorphism of the COMT gene and the GMV/cortical thickness/cortical surface area in 150 first-episode treatment-naïve patients with schizophrenia and 100 healthy controls. Main effects of diagnosis were found for GMV in the cerebellum and the visual, medial temporal, parietal, and middle frontal cortex. Patients with schizophrenia showed reduced GMVs in these regions. And main effects of genotype were detected for GMV in the left superior frontal gyrus. Moreover, a diagnosis × genotype interaction was found for the GMV of the left precuneus, and the effect of the COMT gene on GMV was due mainly to cortical thickness rather than cortical surface area. In addition, a pattern of increased GMV in the precuneus with increasing Met dose found in healthy controls was lost in patients with schizophrenia. These findings suggest that the COMTMet variant is associated with the disruption of dopaminergic influence on gray matter in schizophrenia, and the effect of the COMT gene on GMV in schizophrenia is mainly due to changes in cortical thickness rather than in cortical surface area.Neuroscience Bulletin 01/2015; 31(1). DOI:10.1007/s12264-014-1491-7 · 1.83 Impact Factor
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ABSTRACT: D₁ receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. We used positron emission tomography (PET) and a D1 radiotracer, [¹¹C]NNC112, in drug naïve (DN, n = 12) and drug free (DF, n = 13) patients with schizophrenia and 40 healthy control subjects (HC, n = 40 total, n = 24 per comparison group) matched for age, gender, ethnicity, parental socioeconomic status and cigarette smoking. We measured the binding potential BPP, corrected for partial volume effects. The outcome measure was obtained in cortical and striatal subregions outlined on coregistered individual MRIs. Partial volume effect corrected BPP measures were significantly higher in DN vs controls in cortical regions. No such increases were found in the DF versus controls comparison. Furthermore, in the DF group, DF interval correlated positively with cortical BPP. We conclude that upregulation of D1 receptors in schizophrenia is related to the illness itself and may be corrected and normalized by chronic antipsychotic treatment.Journal of Psychopharmacology 07/2011; 26(6):794-805. DOI:10.1177/0269881111409265 · 2.81 Impact Factor
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ABSTRACT: Non-psychotic individuals at increased risk for schizophrenia show alterations in fronto-striatal dopamine signaling and cortical gray matter maturation reminiscent of those seen in schizophrenia. It remains unclear however if variations in dopamine signaling influence rates of structural cortical maturation in typically developing individuals, and whether such influences are disrupted in patients with schizophrenia and their non-psychotic siblings. We sought to address these issues by relating a functional Val→Met polymorphism within the gene encoding catechol-o-methyltransferase (COMT)-a key enzymatic regulator of cortical dopamine levels-to longitudinal structural neuroimaging measures of cortical gray matter thickness. We included a total of 792 magnetic resonance imaging brain scans, acquired between ages 9 and 22 years from patients with childhood-onset schizophrenia (COS), their non-psychotic full siblings, and matched healthy controls. Whereas greater Val allele dose (which confers enhanced dopamine catabolism and is proposed to aggravate cortical deficits in schizophrenia) accelerated adolescent cortical thinning in both schizophrenia probands and their siblings, it attenuated cortical thinning in healthy controls. This similarity between COS patients and their siblings was accompanied by differences between the two groups in the timing and spatial distribution of disrupted COMT influences on cortical maturation. Consequently, whereas greater Val "dose" conferred persistent dorsolateral prefrontal cortical deficits amongst affected probands by adulthood, cortical thickness differences associated with varying Val dose in non-psychotic siblings resolved over the age-range studied. These findings suggest that cortical abnormalities in pedigrees affected by schizophrenia may be contributed to by a disruption of dopaminergic infleunces on cortical maturation.NeuroImage 05/2011; 57(4):1517-23. DOI:10.1016/j.neuroimage.2011.05.032 · 6.13 Impact Factor