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: Abstract To evaluate the contribution of individual synaptic constituents, all available in vivo imaging studies on schizophrenic patients were subjected to a retrospective analysis. For the pool of drug-naïve, drug-free, and acutely medicated patients, major findings were increases in neostriatal dopamine (DA) synthesis and release and decreases in neostriatal DA transporters and D1 receptors, neostriatal, thalamic, frontal, and parietal D2 receptors, mesencephalic/pontine and temporal 5-HT1A receptors, frontal and temporal HT2A and μ-amino butyric acid (GABA)A receptors. Based on the findings on drug-naïve and drug-free patients, it may be hypothesized that schizophrenia initially is characterized by an impaired mechanism of D2 autoreceptor and heteroreceptor sensitization leading to sensitization instead of desensitization in response to increased levels of neostriatal DA. Neuroleptic medication blocks neostriatal D2 autoreceptor and heteroreceptors, reducing neostriatal DA and disinhibiting DA action mediated by D2 heteroreceptor binding sites. Ultimately, this may result in a restitution of GABA function, leading to a recovery of inhibitory input to the target regions of the descending corticothalamostriatal efferents. Furthermore, a blockade of inhibitory and excitatory neocortical 5-HT function may be inferred, which is likely to reduce (excitatory) DAergic input to the mesolimbic target regions of corticothalamostriatal projections.Reviews in the neurosciences 02/2014; 25(1):25-96. DOI:10.1515/revneuro-2013-0063 · 3.31 Impact Factor
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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: The glutamate and dopamine hypotheses are leading theories of the pathoaetiology of schizophrenia. Both were initially based on indirect evidence from pharmacological studies supported by post-mortem findings, but have since been substantially advanced by new lines of evidence from in vivo imaging studies. This review provides an update on the latest findings on dopamine and glutamate abnormalities in schizophrenia, focusing on in vivo neuroimaging studies in patients and clinical high-risk groups, and considers their implications for understanding the biology and treatment of schizophrenia. These findings have refined both the dopamine and glutamate hypotheses, enabling greater anatomical and functional specificity, and have been complemented by preclinical evidence showing how the risk factors for schizophrenia impact on the dopamine and glutamate systems. The implications of this new evidence for understanding the development and treatment of schizophrenia are considered, and the gaps in current knowledge highlighted. Finally, the evidence for an integrated model of the interactions between the glutamate and dopamine systems is reviewed, and future directions discussed. © The Author(s) 2015.Journal of Psychopharmacology 01/2015; 29(2). DOI:10.1177/0269881114563634 · 2.81 Impact Factor