Molecular imaging studies of the striatal dopaminergic system in psychosis and predictions for the prodromal phase of psychosis

Abstract

The dopamine hypothesis has been the major pathophysiological theory of psychosis in recent decades. Molecular imaging studies have provided in vivo evidence of increased dopamine synaptic availability and increased presynaptic dopamine synthesis in the striata of people with psychotic illnesses. These studies support the predictions of the dopamine hypothesis, but it remains to be determined whether dopaminergic abnormalities pre-date or are secondary to the development of psychosis. We selectively review the molecular imaging studies of the striatal dopaminergic system in psychosis and link this to models of psychosis and the functional subdivisions of the striatum to make predictions for the dopaminergic system in the prodromal phase of psychosis.

Prenatal Immune Activation Interacts with GeneticNurr1Deficiency in the Development of Attentional Impairments

“…In addition to the relevance of increased prefrontal COMT density/activity to schizophrenia (Weinberger et al, 2001;Chen et al, 2004;Tan et al, 2009), our findings of reduced TH fiber density in the mPFC of poly(I:C)-exposed Nurr1 ϩ/Ϫ offspring match postmortem investigations in schizophrenic patients showing reduced densities of TH-immunoreactive axons in specific areas of the PFC (Akil et al, 1999). However, our geneenvironment model falls short in mimicking postmortem and imaging findings implicating a mild but significant elevation of D 2 R densities in striatal structures of schizophrenic patients (Laruelle, 1998;Howes et al, 2007). Furthermore, our study does not reveal a direct relationship between prefrontal dopamine pathology (in the form of reduced and increased TH and COMT density, respectively) and disruption of working memory, the latter of which is presumably dependent on prefrontal dopamine activity (Floresco and Magyar, 2006).…”

“…Imaging studies in humans and experimental work in animals have repeatedly associated abnormal dopaminergic mechanisms especially within mesocortical and frontostriatal pathways in the precipitation of impairments in attentional shifting and sustained attention (Floresco and Magyar, 2006;Kehagia et al, 2010;Cools and D'Esposito, 2011;Del Campo et al, 2011), and dopaminergic imbalances in these pathways have also long been recognized to contribute to the neuropathology of both schizophrenia (Knable and Weinberger, 1997;Howes et al, 2007) and ADHD (Del Campo et al, 2011). Here, we identified a number of neuropathological deficits that are suggestive of dopaminergic imbalances in the mesocortical and frontostriatal pathways.…”

“…The following primary antibodies were used to study dopamine-related markers in various brain areas according to protocols established previously (Meyer et al, 2008a;Bitanihirwe et al, 2010a;Vuillermot et al, 2010): rabbit anti-TH (Santa Cruz Biotechnology; diluted 1:500), rabbit antidopamine D 1 receptor (D 1 R) (Millipore Bioscience Research Reagents; diluted 1:250), rabbit anti-dopamine D 2 receptor (D 2 R) (Millipore Bioscience Research Reagents; diluted 1:500), and rabbit anti-catechol-Omethyltransferase (COMT) (SDI; diluted 1:5000). These dopaminergic markers were selected because they are known to be modulated by prenatal immune activation and/or genetic Nurr1 deficiency (Zetterström et al, 1997;Saucedo-Cardenas et al, 1998;Kadkhodaei et al, 2009;Bitanihirwe et al, 2010a;Vuillermot et al, 2010Vuillermot et al, , 2011c and because they are implicated in the dopaminergic neuropathology of schizophrenia and related disorders (Akil et al, 1999;Chen et al, 2004;Howes et al, 2007). All antibodies were diluted in PBS containing 0.3% Triton X-100 and 2% normal serum, and the sections were incubated free-floating overnight at room temperature.…”

Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis

“…1,2 The increase was localized to the associative subregion of the striatum, which is anatomically and functionally linked to prefrontal cortex. [16][17][18] Moreover, it was correlated with the degree to which performance in the ARMS subjects was impaired on a verbal fluency task, 15 a paradigm that is critically dependent on prefrontal function.…”

“…3,4 In particular, five independent molecular imaging studies have found pre-synaptic dopamine overactivity in patients with schizophrenia and first episode of psychosis (reviewed in Laruelle and Howes et al 1,2 ). Functional imaging studies of tasks that engage executive functions, such as verbal fluency, show differential engagement of the prefrontal cortex in patients with schizophrenia relative to controls, 5-7 even after controlling for impaired task performance.…”