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Presynaptic Dopaminergic Dysfunction in Schizophrenia: A Positron Emission Tomographic [18F]Fluorodopa Study

Cyclotron Unit, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, Imperial College, London, England.
Archives of General Psychiatry (Impact Factor: 13.75). 03/2004; 61(2):134-42. DOI: 10.1001/archpsyc.61.2.134
Source: PubMed

ABSTRACT The dopamine overactivity hypothesis of schizophrenia remains one of the most influential theories of the pathophysiology of the illness. Radiotracer brain imaging studies are now directly testing aspects of the overactivity hypothesis.
To assess presynaptic dopaminergic function in a large cohort of patients with schizophrenia by means of [18F]fluorodopa uptake and a high-sensitivity 3-dimensional positron emission tomograph. We predicted elevations in striatal [18F]fluorodopa uptake and reductions in prefrontal cortical [18F]fluorodopa uptake in patients with schizophrenia.
Case-control study.
Research institute investigation recruiting hospital outpatients.
Sixteen male medicated hospital outpatients with a DSM-IV diagnosis of schizophrenia (mean age, 38 years) and 12 age-matched male volunteers free of psychiatric and neurologic illness.
[18F]fluorodopa positron emission tomographic scanning. MAIN OUTDOME MEASURE: [18F]fluorodopa uptake constant Ki measured with statistical parametric mapping and region-of-interest analyses.
Statistical parametric mapping (P<.05 corrected) and region-of-interest analyses (P<.01) showed increased [18F]fluorodopa uptake, confined primarily to the ventral striatum in patients with schizophrenia. No reductions in prefrontal cortical [18F]fluorodopa uptake Ki were seen in the statistical parametric mapping and region-of-interest analyses, although dorsal anterior cingulate [18F]fluorodopa Ki correlated with performance on the Stroop Color-Word Test in both groups.
As in studies in unmedicated patients, presynaptic striatal dopamine dysfunction is present in medicated schizophrenic patients, adding further in vivo support for dopamine overactivity in the illness.

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    • "We normalised an [ 18 F ] - DOPA template from a previous study ( McGowan et al . 2004 ) with the ROI map to each individual PET summation ( add ) image using statistical para - metric mapping software ( SPM5 , http : / / fil . ion . ucl . ac . uk / spm ) . This allowed us to place ROIs automatically on individual [ 18 F ] - DOPA PET images , thus removing observer bias . ROIs were then double - checked on each subject ' "
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    ABSTRACT: Cannabis is the most widely used illicit drug in the world, and regular use has been associated with reduced motivation, i.e. apathy. Regular long-term cannabis use has been associated with reduced dopamine synthesis capacity. The mesolimbic dopaminergic system mediates the processing of incentive stimuli by modifying their motivational value, which in turn is modulated by endocannabinoid signalling. Thus, it has been proposed that dopaminergic dysfunction underlies the apathy associated with chronic cannabis use. The aim of this study was to examine the relationship between dopaminergic function and subjective apathy in cannabis users. We measured dopamine synthesis capacity (indexed as the influx rate constant K i (cer) ) via 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine positron emission tomography and subjective apathy using the self-rated Apathy Evaluation Scale (AES-S) in 14 regular cannabis users. All subjects scored in excess of 34 points on the AES-S (median [interquartile range] 59.5 [7.5]), indicative of significant apathy based on normative data. K i (cer) was inversely correlated to AES-S score in the whole striatum and its associative functional subdivision (Spearman's rho = -0.64, p = 0.015 [whole striatum]; rho = -0.69, p = 0.006 [associative]) but not in the limbic or sensorimotor striatal subdivisions. There were no significant relationships between AES-S and current cannabis consumption (rho = 0.28, p = 0.34) or age of first cannabis use (rho = 0.25, p = 0.40). These findings indicate that the reduction in striatal dopamine synthesis capacity associated with chronic cannabis use may underlie reduced reward sensitivity and amotivation associated with chronic cannabis use.
    Psychopharmacology 04/2014; 231(11). DOI:10.1007/s00213-014-3523-4 · 3.99 Impact Factor
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    • " a significant elevation in 18 F - DOPA uptake in control subjects , supporting our region of interest findings . An abnormality in the reference region is also unlikely to explain the results as previous studies have reported elevated striatal dopa - mine synthesis capacity in schizophrenia using other reference regions ( Hietala et al . , 1995 ; McGowan et al . , 2004 ) . Partial volume and spill - over effects can affect measurements in small regions of interest but are unlikely to account for the elevation in the nigra as nigral volumes are , if anything , reduced in schizo - phrenia ( Bogerts et al . , 1983 ) , and these effects would thus tend to underestimate the K cer i values . In contrast to "
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    ABSTRACT: Elevated in vivo markers of presynaptic striatal dopamine activity have been a consistent finding in schizophrenia, and include a large effect size elevation in dopamine synthesis capacity. However, it is not known if the dopaminergic dysfunction is limited to the striatal terminals of dopamine neurons, or is also evident in the dopamine neuron cell bodies, which mostly originate in the substantia nigra. The aim of our studies was therefore to determine whether dopamine synthesis capacity is altered in the substantia nigra of people with schizophrenia, and how this relates to symptoms. In a post-mortem study, a semi-quantitative analysis of tyrosine hydroxylase staining was conducted in nigral dopaminergic cells from post-mortem tissue from patients with schizophrenia (n = 12), major depressive disorder (n = 13) and matched control subjects (n = 13). In an in vivo imaging study, nigral and striatal dopaminergic function was measured in patients with schizophrenia (n = 29) and matched healthy control subjects (n = 29) using (18)F-dihydroxyphenyl-l-alanine ((18)F-DOPA) positron emission tomography. In the post-mortem study we found that tyrosine hydroxylase staining was significantly increased in nigral dopaminergic neurons in schizophrenia compared with both control subjects (P < 0.001) and major depressive disorder (P < 0.001). There was no significant difference in tyrosine hydroxylase staining between control subjects and patients with major depressive disorder, indicating that the elevation in schizophrenia is not a non-specific indicator of psychiatric illness. In the in vivo imaging study we found that (18)F-dihydroxyphenyl-l-alanine uptake was elevated in both the substantia nigra and in the striatum of patients with schizophrenia (effect sizes = 0.85, P = 0.003 and 1.14, P < 0.0001, respectively) and, in the voxel-based analysis, was elevated in the right nigra (P < 0.05 corrected for family wise-error). Furthermore, nigral (18)F-dihydroxyphenyl-l-alanine uptake was positively related with the severity of symptoms (r = 0.39, P = 0.035) in patients. However, whereas nigral and striatal (18)F-dihydroxyphenyl-l-alanine uptake were positively related in control subjects (r = 0.63, P < 0.001), this was not the case in patients (r = 0.30, P = 0.11). These findings indicate that elevated dopamine synthesis capacity is seen in the nigral origin of dopamine neurons as well as their striatal terminals in schizophrenia, and is linked to symptom severity in patients.
    Brain 10/2013; 136(11). DOI:10.1093/brain/awt264 · 10.23 Impact Factor
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    • "However, there are, to date, certain findings with a considerable replication that could support the hypothesis of common mechanisms or at least final common pathways for schizophrenia or most cases within that label. One is the increased dopamine presynaptic synthesis (Elkashef et al., 2000; Hietala et al., 1995; Howes et al., 2009; Kumakura et al., 2007; McGowan et al., 2004) and release in response to an amphetamine challenge (Abi-Dargham et al., 2004; Laruelle, 1998) in comparison with healthy controls. Another is the relative deficit in GABA-mediated inhibitory transmission in the cerebral cortex (Lewis et al., 2005), specially supported by reductions of glutamate decarboxylase, isoform 67; messenger RNA (Akbarian et al., 1995; Guidotti et al., 2000; Thompson et al., 2009; Volk et al., 2000); and reelin (Guidotti et al., 2000; Hossein Fatemi et al., 2005; Impagnatiello et al., 1998). "
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    ABSTRACT: The current schizophrenia concept is built on experts' agreement on the matter, and it is basically rooted in the epidemiological and clinical evidence. However, the numerous and intensive attempts to find the biological underpinnings of this syndrome face almost constantly a low degree of replication of the results. We have reviewed previously published work to contribute to identify some reasons underlying that failure. The difficulty in replicating biological findings in schizophrenia may relate to the intrinsic heterogeneity among patient samples, acquired through the current diagnostic criteria. As a result, the necessary replication for any finding to be accepted as characteristic data for schizophrenia would be impeded. Therefore, a new frame based on identification of correlates of the most replicated biological anomalies in schizophrenia to date may contribute to overcome those difficulties.
    The Journal of nervous and mental disease 09/2013; 201(9):744-52. DOI:10.1097/NMD.0b013e3182a21444 · 1.81 Impact Factor
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