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1.  Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study 
Brain  2013;136(11):3242-3251.
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 18F-dihydroxyphenyl-l-alanine (18F-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 18F-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 18F-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 18F-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.
doi:10.1093/brain/awt264
PMCID: PMC3808688  PMID: 24097339
dopamine; psychosis; depression; substantia nigra; schizophrenia; F-DOPA; dihydroxyphenyl-l-alanine; brain imaging; striatum; tyrosine; post-mortem
2.  Acute effect of the anti-addiction drug bupropion on extracellular dopamine concentrations in the human striatum: An [11C]raclopride PET study 
NeuroImage  2009;50(1):260-266.
Bupropion is an effective medication in treating addiction and is widely used as an aid to smoking cessation. Bupropion inhibits striatal dopamine reuptake via dopamine transporter blockade, but it is unknown whether this leads to increased extracellular dopamine levels at clinical doses in man. The effects of bupropion on extracellular dopamine levels in the striatum were investigated using [11C]raclopride positron emission tomography (PET) imaging in rats administered saline, 11 or 25mg/kg bupropion i.p. and in healthy human volunteers administered either placebo or 150mg bupropion (Zyban® Sustained-Release). A cognitive task was used to stimulate dopamine release in the human study. In rats, bupropion significantly decreased [11C]raclopride specific binding in the striatum, consistent with increases in extracellular dopamine concentrations. In man, no significant decreases in striatal [11C]raclopride specific binding were observed. Levels of dopamine transporter occupancy in the rat at 11 and 25mg/kg bupropion i.p. were higher than predicted to occur in man at the dose used. Thus, these data indicate that, at the low levels of dopamine transporter occupancy achieved in man at clinical doses, bupropion does not increase extracellular dopamine levels. These findings have important implications for understanding the mechanism of action underlying bupropions’ therapeutic efficacy and for the development of novel treatments for addiction and depression.
doi:10.1016/j.neuroimage.2009.11.077
PMCID: PMC4135078  PMID: 19969097
bupropion; dopamine; imaging positron emission tomography; [11C]raclopride; striatum; addiction, depression, mechanism, smoking, rat, human
3.  Further evaluation of the carbon11-labelled D2/3 agonist PET radiotracer PHNO: reproducibility in tracer characteristics and characterization of extrastriatal binding 
Synapse (New York, N.Y.)  2010;64(4):301-312.
[11C]-(+)-PHNO is a new dopamine D2/3 receptor agonist radiotracer which has been successfully used to measure D2/3 receptor availability in experimental animals and man. Here we report in vivo evaluation in the rat of the biodistribution, metabolism, specificity, selectivity and dopamine sensitivity of carbon-11 labeled PHNO ([11C]-3-PHNO) produced by an alternative radiochemical synthesis method. [11C]-3-PHNO showed rapid metabolism and clearance from most peripheral organs and tissues. [11C]-3-PHNO, but not its polar metabolite, readily crossed the blood-brain barrier and showed high levels of uptake in the D2/3 -rich striatum. Pre-treatment with unlabelled PHNO and the D2/3 receptor antagonist raclopride indicated that binding in the striatum was specific and selective to D2/3 receptors. PET studies in anaesthetized rats revealed significant reductions in [11C]-3-PHNO binding in the striatum following amphetamine administration, indicating sensitivity to increases in endogenous dopamine concentrations. D2/3 antagonist pre-treatment additionally indicated moderate levels of [11C]-3-PHNO specific binding in several extrastriatal brain areas – most notably the olfactory bulbs and tubercles, thalamus and hypothalamus. Of particular interest, approximately 30% of [11C]-3-PHNO signal in the cerebellum – a region often used as a ‘low-binding’ reference region for PET quantification - was attributable to specific signal. These data demonstrate that [11C]-3-PHNO shows similar tracer characteristics to [11C]-(+)-PHNO, but additionally indicate that radiolabeled PHNO may be used to estimate D2/3 receptor availability in select extrastriatal brain regions with PET.
doi:10.1002/syn.20718
PMCID: PMC4134877  PMID: 19957364
PHNO; PET; dopamine; D2high; extrastriatal
4.  The test-retest reliability of 18F-DOPA PET in assessing striatal and extrastriatal presynaptic dopaminergic function 
NeuroImage  2009;50(2):524-531.
Brain presynaptic dopaminergic function can be assessed using 18F-DOPA positron emission tomography (PET). Regional 18F-DOPA utilization may be used to index dopaminergic abnormalities over time or dopaminergic response to treatment in clinical populations. Such studies require prior knowledge of the stability of the 18F-DOPA signal in the brain regions of interest. Test-retest reliability was examined in eight healthy volunteers who each received two 18F-DOPA PET scans, approximately two years apart. 18F-DOPA utilization (kicer) was determined using graphical analysis relative to a reference tissue input (Patlak et al., 1983). Reproducibility (measured as the within-subjects variation) and reliability (measured as intraclass correlation coefficients, ICCs), of 18F-DOPA kicer was assessed in the structural and functional subdivisions of the striatum and select extrastriatal brain regions. Voxel-based median ICC maps were used to visualize the distribution of 18F-DOPA kicer reliability across the brain. The caudate and putamen, and associative and sensorimotor, striatal subdivisions showed good reliability across the two scan sessions with bilateral ICCs ranging from 0.681 to 0.944. Reliability was generally lower in extrastriatal regions, with bilateral ICCs ranging from 0.235 in the amygdala to 0.894 in the thalamus. These data confirm the utility of 18F-DOPA PET in assessing dopaminergic function in the striatum and select extrastriatal areas, but highlight the limitations in using this approach to measure dopaminergic function in low uptake extrastriatal brain areas. This information can be used to optimize the experimental design of future studies investigating changes in brain dopaminergic function with 18F-DOPA.
doi:10.1016/j.neuroimage.2009.12.058
PMCID: PMC4096947  PMID: 20034580
Dopamine; Positron Emission Tomography; 18F-DOPA; Striatum; Reproducibility, Reliability; Schizophrenia; Parkinson’s disease, longitudinal, extrastriatal
5.  Relationship between Glutamate Dysfunction and Symptoms and Cognitive Function in Psychosis 
The glutamate hypothesis of schizophrenia, proposed over two decades ago, originated following the observation that administration of drugs that block NMDA glutamate receptors, such as ketamine, could induce schizophrenia-like symptoms. Since then, this hypothesis has been extended to describe how glutamate abnormalities may disturb brain function and underpin psychotic symptoms and cognitive impairments. The glutamatergic system is now a major focus for the development of new compounds in schizophrenia. Relationships between regional brain glutamate function and symptom severity can be investigated using proton magnetic resonance spectroscopy (1H-MRS) to estimate levels of glutamatergic metabolites in vivo. Here we briefly review the 1H-MRS studies that have explored relationships between glutamatergic metabolites, symptoms, and cognitive function in clinical samples. While some of these studies suggest that more severe symptoms may be associated with elevated glutamatergic function in the anterior cingulate, studies in larger patient samples selected on the basis of symptom severity are required.
doi:10.3389/fpsyt.2013.00151
PMCID: PMC3840324  PMID: 24324444
schizophrenia; psychosis; glutamate; NMDA; MRS; spectroscopy; imaging
6.  Transition to Psychosis Associated With Prefrontal and Subcortical Dysfunction in Ultra High-Risk Individuals 
Schizophrenia Bulletin  2012;38(6):1268-1276.
Background: People at ultra high risk (UHR) of psychosis have an elevated risk of developing a psychotic disorder, but it is difficult to predict which individuals will make a transition to frank illness. We investigated whether functional magnetic resonance imaging (fMRI) in conjunction with a phonological fluency task at presentation could distinguish subjects who subsequently developed psychosis from those who did not. Methods: Sixty-five subjects (41 with an UHR and 24 healthy controls) were assessed at clinical presentation using fMRI, in conjunction with a verbal fluency task. [18F]-DOPA positron emission tomography (PET) data were also available in a subgroup of 21 UHR and 14 healthy controls subjects. UHR subjects were followed clinically for at least 2 years. Results: Compared with UHR subjects who did not become psychotic, UHR subjects who subsequently developed psychosis showed increased activation in bilateral prefrontal cortex (PFC), brainstem (midbrain/basilar pons), the left hippocampus, and greater midbrain-PFC connectivity. Furthermore, exploratory analysis of [18F]-DOPA PET data showed that transition to psychosis was associated with elevated dopaminergic function in the brainstem region. Conclusions: In people at high risk of psychosis, increased activation in a network of cortical and subcortical regions may predict the subsequent onset of illness. Functional neuroimaging, in conjunction with clinical assessment and other investigations, may facilitate the prediction of outcome in subjects who are vulnerable to psychosis.
doi:10.1093/schbul/sbr194
PMCID: PMC3494046  PMID: 22290265
prodromal psychosis; schizophrenia; prefrontal cortex; dopamine; MRI; 18F-DOPA PET
7.  The dopaminergic basis of human behaviors: a review of molecular imaging studies 
This systematic review describes human molecular imaging studies which have investigated alterations in extracellular DA levels during performance of behavioral tasks. Whilst heterogeneity in experimental methods limits meta-analysis, we describe the advantages and limitations of different methodological approaches. Interpretation of experimental results may be limited by regional cerebral blood flow (rCBF) changes, head movement and choice of control conditions. We revisit our original study of striatal DA release during video-game playing (Koepp et al., 1998) to illustrate the potentially confounding influences of head movement and alterations in rCBF. Changes in [11C]raclopride binding may be detected in extrastriatal as well as striatal brain regions – however we review evidence which suggests that extrastriatal changes may not be clearly interpreted in terms of DA release. Whilst several investigations have detected increases in striatal extracellular DA concentrations during task components such as motor learning and execution, reward-related processes, stress and cognitive performance, the presence of potentially biasing factors should be carefully considered (and, where possible, accounted for) when designing and interpreting future studies.
doi:10.1016/j.neubiorev.2009.05.005
PMCID: PMC3797507  PMID: 19481108
Dopamine; PET; SPET; striatum; D2/3 receptor; [11C]raclopride; cognition; reward; stress; motor
8.  Anterior Cingulate Glutamate Levels Related to Clinical Status Following Treatment in First-Episode Schizophrenia 
Neuropsychopharmacology  2012;37(11):2515-2521.
Many patients with schizophrenia show a limited symptomatic response to treatment with dopaminergic antipsychotics. This may reflect the additional involvement of non-dopaminergic neurochemical dysfunction in the pathophysiology of the disorder. We tested the hypothesis that brain glutamate levels would differ between patients with first-episode psychosis who were symptomatic compared with those with minimal symptoms following antipsychotic treatment. Proton magnetic resonance spectroscopy (1H-MRS) spectra were acquired at 3 Tesla in the anterior cingulate cortex and left thalamus in 15 patients with first-episode psychosis in symptomatic remission, and 17 patients with first-episode psychosis who were still symptomatic following at least one course of antipsychotic treatment. Metabolite levels were estimated in ratio to creatine (Cr) using LCModel. Levels of glutamate/Cr in the anterior cingulate cortex were significantly higher in patients who were still symptomatic than in those in remission (T(30)=3.02; P=0.005). Across the entire sample, higher levels of glutamate/Cr in the anterior cingulate cortex were associated with a greater severity of negative symptoms (r=0.42; P=0.017) and a lower level of global functioning (r=−0.47; P=0.007). These findings suggest that clinical status following antipsychotic treatment in schizophrenia is linked to glutamate dysfunction. Treatment with compounds acting on the glutamatergic system might therefore be beneficial in patients who respond poorly to dopaminergic antipsychotics.
doi:10.1038/npp.2012.113
PMCID: PMC3442346  PMID: 22763619
psychosis; magnetic resonance spectroscopy; glutamate; treatment response; anterior cingulate cortex; thalamus; glutamate, schizophrenia/antipsychotics, imaging, clinical or preclinical, biological psychiatry, psychosis, anterior cingulate cortex, thalamus, magnetic resonance spectroscopy, treatment response
9.  Abnormal Relationship Between Medial Temporal Lobe and Subcortical Dopamine Function in People With an Ultra High Risk for Psychosis 
Schizophrenia Bulletin  2011;38(5):1040-1049.
Background: Neuroimaging studies in humans have implicated both dysfunction of the medial temporal lobe (MTL) and the dopamine system in psychosis, but the relationship between them is unclear. We addressed this issue by measuring MTL activation and striatal dopaminergic function in individuals with an At Risk Mental State (ARMS) for psychosis, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), respectively. Methods: Thirty-four subjects (20 ARMS and 14 Controls), matched for age, gender, digit span performance, and premorbid IQ, were scanned using fMRI, while performing a verbal encoding and recognition task, and using 18F-DOPA PET. All participants were naïve to antipsychotic medication. Results: ARMS subjects showed reduced MTL activation when encoding words and made more false alarm responses for Novel words than controls. The relationship between striatal dopamine function and MTL activation during both verbal encoding and verbal recognition was significantly different in ARMS subjects compared with controls. Conclusion: An altered relationship between MTL function and dopamine storage/synthesis capacity exists in the ARMS and may be related to psychosis vulnerability.
doi:10.1093/schbul/sbr017
PMCID: PMC3446221  PMID: 21536784
psychosis; prodromal; dopamine; medial temporal lobe; schizophrenia; PET; MRI
10.  Dopamine synthesis capacity prior to the subsequent onset of psychosis: an [18F]-DOPA PET imaging study 
The American journal of psychiatry  2011;168(12):1311-1317.
Objective
Whilst there is robust evidence of elevated dopamine synthesis capacity once a psychotic disorder has developed, little is known about whether it is altered prior to the first episode of frank illness. We addressed this issue by measuring dopamine synthesis capacity in subjects at ultra high risk of psychosis, and then following them to determine their clinical outcome.
Method
This prospective study included thirty subjects who met standard criteria for being at ultra high risk of psychosis and twenty-nine healthy volunteers. Subjects were scanned using [18F]-DOPA positron emission tomography. The ultra high risk subjects were scanned at presentation and followed-up for at least three years to determine their clinical outcome. Six subjects had co-morbid schizotypal personality disorder and were excluded from the analysis (data are provided for comparison). Of the remaining subjects, nine developed a psychotic disorder subsequent to scanning (psychotic transition group), and 15 did not (non-transition group).
Results
There was a significant effect of group on striatal dopamine synthesis capacity (p=0.006). The psychotic transition group had greater dopamine synthesis capacity in the striatum (p=0.004, effect size=1.18) and its associative subdivision (p=0.015, effect size=1.24) than controls, and showed a positive correlation between dopamine synthesis capacity and symptom severity. Dopamine synthesis capacity was also significantly greater in the psychotic transition than the non-transition group (p=0.036).
Conclusions
These findings provide evidence that the onset of frank psychosis is preceded by presynaptic dopaminergic dysfunction. Further work is required to determine the specificity of elevated dopamine synthesis capacity to particular psychotic disorders.
doi:10.1176/appi.ajp.2011.11010160
PMCID: PMC3682447  PMID: 21768612
psychosis; schizophrenia; prodrome; at risk; vulnerability; dopamine; imaging; cause; pathophysiology; hypothesis; bipolar affective disorder; schizotypal personality disorder; psychosis continuum; psychosis spectrum
11.  Striatal dopamine D2/D3 receptor binding in pathological gambling is correlated with mood-related impulsivity 
Neuroimage  2012;63(1):40-46.
Pathological gambling (PG) is a behavioural addiction associated with elevated impulsivity and suspected dopamine dysregulation. Reduced striatal dopamine D2/D3 receptor availability has been reported in drug addiction, and may constitute a premorbid vulnerability marker for addictive disorders. The aim of the present study was to assess striatal dopamine D2/D3 receptor availability in PG, and its association with trait impulsivity. Males with PG (n = 9) and male healthy controls (n = 9) underwent [11C]-raclopride positron emission tomography imaging and completed the UPPS-P impulsivity scale. There was no significant difference between groups in striatal dopamine D2/D3 receptor availability, in contrast to previous reports in drug addiction. However, mood-related impulsivity (‘Urgency’) was negatively correlated with [11C]-raclopride binding potentials in the PG group. The absence of a group difference in striatal dopamine binding implies a distinction between behavioural addictions and drug addictions. Nevertheless, our data indicate heterogeneity in dopamine receptor availability in disordered gambling, such that individuals with high mood-related impulsivity may show differential benefits from dopamine-based medications.
Highlights
► Assessed 11C-raclopride binding in pathological gambling, a putative behavioral addiction. ► No group difference in striatal dopamine binding from healthy controls. ► Dopamine binding negatively correlated with mood-related impulsivity (‘Urgency’).
doi:10.1016/j.neuroimage.2012.06.067
PMCID: PMC3438449  PMID: 22776462
Gambling; Impulsivity; Dopamine; Neuroimaging; Addiction; Striatum

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