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1.  Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers 
Neuropsychopharmacology  2015;41(7):1742-1750.
Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [11C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [11C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [11C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [11C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions.
PMCID: PMC4869041  PMID: 26552847
2.  Further human evidence for striatal dopamine release induced by administration of Δ9-tetrahydrocannabinol (THC): selectivity to limbic striatum 
Psychopharmacology  2015;232(15):2723-2729.
Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of Δ9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results.
To assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants.
We combined human neurochemical imaging data from two previous studies that used [11C]raclopride positron emission tomography (PET) (n=7 and n=13, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis.
THC administration induced a significant reduction in [11C]raclopride binding in the limbic striatum (−3.65%, from 2.39±0.26 to 2.30±0.23, p=0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions.
In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release, and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.
PMCID: PMC4816196  PMID: 25801289
Dopamine; positron emission tomography (PET); Δ9-tetrahydrocannabinol (THC); [11C]raclopride; striatum; cannabis
3.  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.
PMCID: PMC4135078  PMID: 19969097
bupropion; dopamine; imaging positron emission tomography; [11C]raclopride; striatum; addiction, depression, mechanism, smoking, rat, human
4.  Nature or Nurture? Determining the Heritability of Human Striatal Dopamine Function: an [18F]-DOPA PET Study 
Neuropsychopharmacology  2012;38(3):485-491.
Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions.
PMCID: PMC3547199  PMID: 23093224
twin; PET; dopamine; heritability; [18F]-DOPA; environment; [18F]-DOPA; Dopamine; Environment; Heritability; Imaging; Clinical or Preclinical; Neurochemistry; PET; Psychiatry & Behavioral Sciences; Striatum; Twin
5.  Frequency and Neural Correlates of Pauses in Patients with Formal Thought Disorder 
Background: Pauses during speech may reflect the planning and monitoring of discourse, two processes putatively impaired in patients with schizophrenia, particularly those with formal thought disorder (FTD). We used functional MRI to examine the neural correlates of between-clause and of filled pauses, which are respectively associated with speech planning and speech monitoring.
Methods: BOLD contrast was measured while six schizophrenia patients with FTD and six healthy subjects spoke about Rorshach inkblots. In an event-related design, we examined activity associated with pauses that occurred between clauses and with pauses that were filled.
Results: There was no significant group difference in the frequency of between-clause pauses but patients with FTD made strikingly fewer filled pauses than controls. Between-clause pauses were associated with activation in the anterior part of the left superior temporal gyrus (STG) and the left insula in controls and the engagement of these regions was significantly attenuated in patients.
Conclusion: The anterior part of the left STG and the left insula are normally involved in both the planning and monitoring of discourse. The attenuated engagement of these regions with between-clause pauses and the striking infrequency of filled pauses in the patients are consistent with cognitive models implicating defective speech planning and speech monitoring in schizophrenia, especially in relation to FTD.
PMCID: PMC3794379  PMID: 24133459
schizophrenia; formal thought disorder; pause; language; fMRI; speech planning; speech monitoring
6.  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.
► 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’).
PMCID: PMC3438449  PMID: 22776462
Gambling; Impulsivity; Dopamine; Neuroimaging; Addiction; Striatum
7.  The Effects of The COMT val108/158met Polymorphism on BOLD Activation During Working Memory, Planning, and Response Inhibition: A Role for The Posterior Cingulate Cortex? 
Neuropsychopharmacology  2010;36(4):763-771.
Catechol-O-methyl transferase (COMT) val108/158met polymorphism impacts on cortical dopamine levels and may influence functional magnetic resonance (fMRI) measures of task-related neuronal activity. Here, we investigate whether COMT genotype influences cortical activations, particularly prefrontal activations, by interrogating its effect across three tasks that have been associated with the dopaminergic system in a large cohort of healthy volunteers. A total of 50 participants (13 met/met, 23 val/met, and 14 val/val) successfully completed N-Back, Go-NoGo, and Tower of London fMRI tasks. Image analysis was performed using statistical parametric mapping. No significant relationships between COMT genotype groups and frontal lobe activations were observed for any contrast of the three tasks studied. However, the val/val group produced significantly greater deactivation of the right posterior cingulate cortex in two tasks: the Go-NoGo (NoGo vs Go deactivation contrast) and N-Back (2-back vs rest deactivation contrast). For the N-Back task, the modulated deactivation cluster was functionally connected to the precuneus, left middle occipital lobe, and cerebellum. These results do not support findings of prefrontal cortical modulation of activity with COMT genotype, but instead suggest that COMT val/val genotype can modulate the activity of the posterior cingulate and may indicate the potential network effects of COMT genotype on the default mode network.
PMCID: PMC3055733  PMID: 21150912
cognition; COMT; default mode network; dopamine; fMRI; frontal; dopamine; imaging; clinical or preclinical; neurogenetics; learning and memory; COMT; cingulated; frontal; fMRI; default mode network
8.  Executive Functions and Prefrontal Cortex: A Matter of Persistence? 
Executive function is thought to originates from the dynamics of frontal cortical networks. We examined the dynamic properties of the blood oxygen level dependent time-series measured with functional MRI (fMRI) within the prefrontal cortex (PFC) to test the hypothesis that temporally persistent neural activity underlies performance in three tasks of executive function. A numerical estimate of signal persistence, the Hurst exponent, postulated to represent the coherent firing of cortical networks, was determined and correlated with task performance. Increasing persistence in the lateral PFC was shown to correlate with improved performance during an n-back task. Conversely, we observed a correlation between persistence and increasing commission error – indicating a failure to inhibit a prepotent response – during a Go/No-Go task. We propose that persistence within the PFC reflects dynamic network formation and these findings underline the importance of frequency analysis of fMRI time-series in the study of executive functions.
PMCID: PMC3031025  PMID: 21286223
executive function; prefrontal cortex; persistence; BOLD; Hurst exponent; networks; functional MRI
9.  Investigating expectation and reward in human opioid addiction with [11C]raclopride PET 
Addiction Biology  2013;19(6):1032-1040.
The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized. We examined whether heroin and the expectation of heroin reward increases striatal dopamine levels in human opioid addiction. Ten opioid-dependent participants maintained on either methadone or buprenorphine underwent [11C]raclopride positron emission tomography imaging. Opioid-dependent participants were scanned three times, receiving reward from 50-mg intravenous heroin (diamorphine; pharmaceutical heroin) during the first scan to generate expectation of the same reward at the second scan, during which they only received 0.1-mg intravenous heroin. There was no heroin injection during the third scan. Intravenous 50-mg heroin during the first scan induced pronounced effects leading to high levels of expectation at the second scan. There was no detectable increase in striatal dopamine levels to either heroin reward or expectation of reward. We believe this is the first human study to examine whether expectation of heroin reward increases striatal dopamine levels in opioid addiction. The absence of detectable increased dopamine levels to both the expectation and delivery of a heroin-related reward may have been due to the impact of substitute medication. It does however contrast with the changes seen in abstinent stimulant users, suggesting that striatal dopamine release alone may not play such a pivotal role in opioid-maintained individuals.
PMCID: PMC4282066  PMID: 23829344
Addiction; dopamine; expectation; heroin; opioid; PET

Results 1-9 (9)