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: 14.48). 03/2004; 61(2):134-42. DOI: 10.1001/archpsyc.61.2.134
Source: PubMed


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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    • "An association between aberrant dopamine neurotransmission is not only correlated with positive symptoms of the disease39,41 but has also been suggestive to be a contributing factor to cognitive deficits observed in patients.47,49 In contrast to that observed in the mesolimbic system, a decrease in dopamine transmission to the cortex may underlie deficits in working memory and executive function.50 "
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    ABSTRACT: Schizophrenia is a disease affecting up to 1% of the population. Current therapies are based on the efficacy of chlorpromazine, discovered over 50 years ago. These drugs block dopamine D2-like receptors and are effective at primarily treating positive symptoms in a subset of patients. Unfortunately, current therapies are far from adequate, and novel treatments require a better understanding of disease pathophysiology. Here we review the dopamine, gamma-aminobutyric acid (GABA), and glutamate hypotheses of schizophrenia and describe a pathway whereby a loss of inhibitory signaling in ventral regions of the hippocampus actually drives a dopamine hyperfunction. Moreover, we discuss novel therapeutic approaches aimed at attenuating ventral hippocampal activity in a preclinical model of schizophrenia, namely the MAM GD17 rat. Specifically, pharmacological (allosteric modulators of the α5 GABAA receptor), neurosurgical (deep brain stimulation), and cell-based (GABAergic precursor transplants) therapies are discussed. By better understanding the underlying circuit level dysfunctions in schizophrenia, novel treatments can be advanced that may provide better efficacy and a superior side effect profile to conventional antipsychotic medications.
    Drug Design, Development and Therapy 07/2014; 8:887-896. DOI:10.2147/DDDT.S42708 · 3.03 Impact Factor
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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 · 3.88 Impact Factor
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    • "For our striatal ROIs, the volume was subdivided as follows: all planes containing striatal structures below the anterior commissure-posterior commissure plane were operationally defined as the ventral striatum (VS) ROI, and all planes above the anterior commissure-posterior commissure plane containing striatal structures formed the dorsal striatum (DS) ROI. The standard object map was applied to the transformed Ki maps and values of FDOPA Ki (units: ml • g−1 • min−1) were obtained for the two striatal ROIs for each individual (McGowan et al., 2004). When performing our ROI analysis a manual correction for head movement was applied as previously described (Whone et al., 2003). "
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    ABSTRACT: Pathological gambling, alongside addictive and antisocial disorders, forms part of a broad psychopathological spectrum of externalizing disorders, which share an underlying genetic vulnerability. The shared externalizing propensity is a highly heritable, continuously varying trait. Disinhibitory personality traits such as impulsivity and novelty seeking (NS) function as indicators of this broad shared externalizing tendency, which may reflect, at the neurobiological level, variation in the reactivity of dopaminergic (DAergic) brain reward systems centered on the ventral striatum (VS). Here, we examined whether individual differences in ventral striatal dopamine (DA) synthesis capacity were associated with individual variation in disinhibitory personality traits. Twelve healthy male volunteers underwent 6-[(18)F]Fluoro-L-DOPA (FDOPA) positron emission tomography (PET) scanning to measure striatal DA synthesis capacity, and completed a measure of disinhibited personality (NS). We found that levels of ventral, but not dorsal, striatal DA synthesis capacity were significantly correlated with inter-individual variation in disinhibitory personality traits, particularly a propensity for financial extravagance and irresponsibility. Our results are consistent with preclinical models of behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of personality based vulnerability to pathological gambling and other externalizing disorders.
    Frontiers in Behavioral Neuroscience 03/2014; 8:86. DOI:10.3389/fnbeh.2014.00086 · 3.27 Impact Factor
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