The Imperial College Cambridge Manchester (ICCAM) platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part A: Study description
Restricted accessResearch articleFirst published online September, 2015
The Imperial College Cambridge Manchester (ICCAM) platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part A: Study description
Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and an evocative images task, using selective antagonists for µ-opioid, dopamine D3 receptor (DRD3) and neurokinin 1 (NK1) receptors (naltrexone, GSK598809, vofopitant/aprepitant), in a placebo-controlled, randomised, crossover design. In two years, 609 scans were performed, with 155 individuals scanned at baseline. Attrition was low and the majority of individuals were sufficiently motivated to complete all five sessions (n=87). We describe herein the study design, main aims, recruitment numbers, sample characteristics, and explain the test hypotheses and anticipated study outputs.
Advisory Council on the Misuse of Drugs (2013) What recovery outcomes does the evidence tell us we can expect? Second report of the Recovery Committee, November 2013. London: Home Office.
2.
Aguilar de ArcosFVerdejo-GarciaACeverinoA. (2008) Dysregulation of emotional response in current and abstinent heroin users: Negative heightening and positive blunting. Psychopharmacology (Berl)198: 159–166.
3.
Aguilar de ArcosFVerdejo-GarciaAPeralta-RamirezMI. (2005) Experience of emotions in substance abusers exposed to images containing neutral, positive, and negative affective stimuli. Drug Alcohol Depend78: 159–167.
4.
American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders. 4th edition, text revised., Washington, DC: American Psychiatric Association.
5.
AntonRFOrosziGO’MalleyS. (2008) An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: Results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry65: 135–144.
6.
AronARFletcherPCBullmoreET. (2003) Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat Neurosci6: 115–116.
7.
AronARRobbinsTWPoldrackRA (2014) Inhibition and the right inferior frontal cortex: One decade on. Trends Cogn Sci18: 177–185.
8.
AsensioSRomeroMJPalauC. (2010) Altered neural response of the appetitive emotional system in cocaine addiction: An fMRI Study. Addict Biol15: 504–516.
BeckASchlagenhaufFWustenbergT. (2009) Ventral striatal activation during reward anticipation correlates with impulsivity in alcoholics. Biol Psychiatry66: 734–742.
11.
BergstromMHargreavesRJBurnsHD. (2004) Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry55: 1007–1012.
12.
BerrySMConnorJTLewisRJ (2015) The platform trial: An efficient strategy for evaluating multiple treatments. JAMA313:1619–1620.
13.
BoileauIAssaadJMPihlRO. (2003) Alcohol promotes dopamine release in the human nucleus accumbens. Synapse49: 226–231.
14.
BoileauIPayerDChuganiB. (2013) The D2/3 dopamine receptor in pathological gambling. A positron emission tomography study with [11C]-(+)-propyl-hexahydro-naphtho-oxazin and [11C]raclopride. Addiction108: 953–963.
15.
BrewerJAWorhunskyPDCarrollKM. (2008) Pretreatment brain activation during stroop task is associated with outcomes in cocaine-dependent patients. Biol Psychiatry64: 998–1004.
16.
BustamanteJCBarros-LoscertalesACostumeroV. (2014) Abstinence duration modulates striatal functioning during monetary reward processing in cocaine patients. Addict Biol19: 885–894.
17.
CarterCSBraverTSBarchDM. (1998) Anterior cingulate cortex, error detection, and the online monitoring of performance. Science280: 747–749.
18.
ChaseHWEickhoffSBLairdAR. (2011) The neural basis of drug stimulus processing and craving: An activation likelihood estimation meta-analysis. Biol Psychiatry70: 785–793.
19.
ChildressARMozleyPDMcElginW. (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry156: 11–18.
20.
CommonsKG (2010) Neuronal pathways linking substance P to drug addiction and stress. Brain Res1314: 175–182.
21.
ConnollyCGFoxeJJNierenbergJ. (2012) The neurobiology of cognitive control in successful cocaine abstinence. Drug Alcohol Depend121: 45–53.
22.
CriaudMBoulinguezP (2013) Have we been asking the right questions when assessing response inhibition in go/no-go tasks with fMRI? A meta-analysis and critical review. Neurosci Biobehav Rev37: 11–23.
23.
CrockettMJClarkLRobbinsTW (2009) Reconciling the role of serotonin in behavioral inhibition and aversion: Acute tryptophan depletion abolishes punishment-induced inhibition in humans. J Neurosci29: 11993–11999.
Di CianoPUnderwoodRJHaganJJ. (2003) Attenuation of cue-controlled cocaine-seeking by a selective D3 dopamine receptor antagonist SB-277011-A. Neuropsychopharmacology28: 329–338.
26.
DiemunschPSchoefflerPBryssineB. (1999) Antiemetic activity of the NK1 receptor antagonist GR205171 in the treatment of established postoperative nausea and vomiting after major gynaecological surgery. Br J Anaesth82: 274–276.
27.
DoddsCMO’NeillBBeaverJ. (2012) Effect of the dopamine D3 receptor antagonist GSK598809 on brain responses to rewarding food images in overweight and obese binge eaters. Appetite59: 27–33.
28.
EbnerKMuiggPSingewaldG. (2008) Substance P in stress and anxiety: NK-1 receptor antagonism interacts with key brain areas of the stress circuitry. Ann N Y Acad Sci1144: 61–73.
29.
EbnerKSartoriSBSingewaldN (2009) Tachykinin receptors as therapeutic targets in stress-related disorders. Curr Pharm Des15: 1647–1674.
30.
ElliottRDeakinB (2005) Role of the orbitofrontal cortex in reinforcement processing and inhibitory control: Evidence from functional magnetic resonance imaging studies in healthy human subjects. Int Rev Neurobiol65: 89–116.
31.
ErritzoeDTziortziABargielaD. (2014) In vivo imaging of cerebral dopamine D3 receptors in alcoholism. Neuropsychopharmacology39: 1703–1712.
32.
ErscheKDBullmoreETCraigKJ. (2010a) Influence of compulsivity of drug abuse on dopaminergic modulation of attentional bias in stimulant dependence. Arch Gen Psychiatry67: 632–644.
33.
ErscheKDClarkLLondonM. (2006) Profile of executive and memory function associated with amphetamine and opiate dependence. Neuropsychopharmacology31: 1036–1047.
34.
ErscheKDJonesPSWilliamsGB. (2012) Abnormal brain structure implicated in stimulant drug addiction. Science335: 601–604.
35.
ErscheKDJonesPSWilliamsGB. (2013) Distinctive personality traits and neural correlates associated with stimulant drug use versus familial risk of stimulant dependence. Biol Psychiatry74: 137–144.
36.
ErscheKDRoiserJPAbbottS. (2011a) Response perseveration in stimulant dependence is associated with striatal dysfunction and can be ameliorated by a D(2/3) receptor agonist. Biol Psychiatry70: 754–762.
37.
ErscheKDRoiserJPLucasM. (2011b) Peripheral biomarkers of cognitive response to dopamine receptor agonist treatment. Psychopharmacology (Berl)214: 779–789.
38.
ErscheKDTurtonAJPradhanS. (2010b) Drug addiction endophenotypes: Impulsive versus sensation-seeking personality traits. Biol Psychiatry68: 770–773.
39.
EverittBJRobbinsTW (2005) Neural systems of reinforcement for drug addiction: From actions to habits to compulsion. Nat Neurosci8: 1481–1489.
40.
FilbeyFMClausEAudetteAR. (2008) Exposure to the taste of alcohol elicits activation of the mesocorticolimbic neurocircuitry. Neuropsychopharmacology33: 1391–1401.
FoxHCBergquistKLHongKI. (2007) Stress-induced and alcohol cue-induced craving in recently abstinent alcohol-dependent individuals. Alcohol Clin Exp Res31: 395–403.
44.
GaravanH (2002) Dissociable executive functions in the dynamic control of behavior: Inhibition, error detection, and correction. Neuroimage17: 1820–1829.
45.
GaravanHRossTJKaufmanJ. (2003) A midline dissociation between error-processing and response-conflict monitoring. Neuroimage20: 1132–1139.
46.
GaravanHRossTJSteinEA (1999) Right hemispheric dominance of inhibitory control: An event-related functional MRI study. Proc Natl Acad Sci U S A96: 8301–8306.
47.
GeorgeDTGilmanJHershJ. (2008) Neurokinin 1 receptor antagonism as a possible therapy for alcoholism. Science319: 1536–1539.
48.
GeorgeOKoobGF (2010) Individual differences in prefrontal cortex function and the transition from drug use to drug dependence. Neurosci Biobehav Rev35: 232–247.
49.
GilmanJMHommerDW (2008) Modulation of brain response to emotional images by alcohol cues in alcohol-dependent patients. Addict Biol13: 423–434.
50.
GoldsteinRZVolkowND (2002) Drug addiction and its underlying neurobiological basis: Neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry159: 1642–1652.
51.
GoldsteinRZVolkowND (2011) Dysfunction of the prefrontal cortex in addiction: Neuroimaging findings and clinical implications. Nat Rev Neurosci12: 652–669.
52.
GorelickDAKimYKBencherifB. (2005) Imaging brain mu-opioid receptors in abstinent cocaine users: Time course and relation to cocaine craving. Biol Psychiatry57: 1573–1582.
53.
GrantSLondonEDNewlinDB. (1996) Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci U S A93: 12040–12045.
54.
HaberSNKnutsonB (2010) The reward circuit: Linking primate anatomy and human imaging. Neuropsychopharmacology35: 4–26.
55.
HackLMKalsiGAlievF. (2011) Limited associations of dopamine system genes with alcohol dependence and related traits in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Alcohol Clin Exp Res35: 376–385.
56.
HampshireAChamberlainSRMontiMM. (2010) The role of the right inferior frontal gyrus: Inhibition and attentional control. Neuroimage50: 1313–1319.
57.
HarrisPATaylorRThielkeR. (2009) Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform42: 377–381.
58.
HaslerGLuckenbaughDASnowJ. (2009) Reward processing after catecholamine depletion in unmedicated, remitted subjects with major depressive disorder. Biol Psychiatry66: 201–205.
59.
HeidbrederCAGardnerELXiZX. (2005) The role of central dopamine D3 receptors in drug addiction: A review of pharmacological evidence. Brain Res Brain Res Rev49: 77–105.
60.
HeiligMThorsellASommerWH. (2010) Translating the neuroscience of alcoholism into clinical treatments: From blocking the buzz to curing the blues. Neurosci Biobehav Rev35: 334–344.
61.
HeinzAReimoldMWraseJ. (2005) Correlation of stable elevations in striatal mu-opioid receptor availability in detoxified alcoholic patients with alcohol craving: A positron emission tomography study using carbon 11-labeled carfentanil. Arch Gen Psychiatry62: 57–64.
62.
HesterRGaravanH (2004) Executive dysfunction in cocaine addiction: Evidence for discordant frontal, cingulate, and cerebellar activity. J Neurosci24: 11017–11022.
63.
HolmesAHeiligMRupniakNM. (2003) Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci24: 580–588.
64.
JasminLNarasaiahMTienD (2006) Noradrenaline is necessary for the hedonic properties of addictive drugs. Vascul Pharmacol45: 243–250.
65.
JiaZWorhunskyPDCarrollKM. (2011) An initial study of neural responses to monetary incentives as related to treatment outcome in cocaine dependence. Biol Psychiatry70: 553–560.
66.
KaufmanJNRossTJSteinEA. (2003) Cingulate hypoactivity in cocaine users during a GO-NOGO task as revealed by event-related functional magnetic resonance imaging. J Neurosci23: 7839–7843.
67.
KiltsCDSchweitzerJBQuinnCK. (2001) Neural activity related to drug craving in cocaine addiction. Arch Gen Psychiatry58: 334–341.
KnutsonBBjorkJMFongGW. (2004) Amphetamine modulates human incentive processing. Neuron43: 261–269.
70.
KoobGKreekMJ (2007) Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry164: 1149–1159.
71.
KoobGFVolkowND (2010) Neurocircuitry of addiction. Neuropsychopharmacology35: 217–238.
72.
KringelbachMLRollsET (2004) The functional neuroanatomy of the human orbitofrontal cortex: Evidence from neuroimaging and neuropsychology. Prog Neurobiol72: 341–372.
73.
KuoSCYehYWChenCY. (2014) DRD3 variation associates with early-onset heroin dependence, but not specific personality traits. Prog Neuropsychopharmacol Biol Psychiatry51: 1–8.
74.
LawrenceAJLutyJBogdanNA. (2009) Impulsivity and response inhibition in alcohol dependence and problem gambling. Psychopharmacology (Berl)207: 163–172.
75.
Le FollBGoldbergSRSokoloffP (2005) The dopamine D3 receptor and drug dependence: Effects on reward or beyond?Neuropharmacology49: 525–541.
76.
Le MerrerJBeckerJABefortK. (2009) Reward processing by the opioid system in the brain. Physiol Rev89: 1379–1412.
77.
Le MoalM (2009) Drug abuse: Vulnerability and transition to addiction. Pharmacopsychiatry42: S42–S55.
78.
LeDouxJE (2000) Emotion circuits in the brain. Annu Rev Neurosci23: 155–184.
79.
LeeBLondonEDPoldrackRA. (2009) Striatal dopamine d2/d3 receptor availability is reduced in methamphetamine dependence and is linked to impulsivity. J Neurosci29: 14734–14740.
80.
LeytonMVezinaP (2014) Dopamine ups and downs in vulnerability to addictions: A neurodevelopmental model. Trends Pharmacol Sci35: 268–276.
81.
LiCSSinhaR (2008) Inhibitory control and emotional stress regulation: Neuroimaging evidence for frontal-limbic dysfunction in psycho-stimulant addiction. Neurosci Biobehav Rev32: 581–597.
82.
Lingford-HughesARDaglishMRCStevensonBJ. (2006) Imaging alcohol cue exposure in alcohol dependence using a PET 15O-H20 paradigm: Results from a pilot study. Addict Biol11: 107–115.
83.
Lingford-HughesARWelchSPetersL. (2012) BAP updated guidelines: Evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: Recommendations from BAP. J Psychopharmacol26: 899–952.
84.
LoreeAMLundahlLHLedgerwoodDM (2014) Impulsivity as a predictor of treatment outcome in substance use disorders: Review and synthesis. Drug Alcohol Rev34:119–134.
85.
LyversM (2000) ‘Loss of control’ in alcoholism and drug addiction: A neuroscientific interpretation. Exp Clin Psychopharmacol8: 225–249.
86.
McCabeCCowenPJHarmerCJ (2009) NK1 receptor antagonism and the neural processing of emotional information in healthy volunteers. Int J Neuropsychopharmacol12: 1261–1274.
87.
MajumdarAKHowardLGoldbergMR. (2006) Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers. J Clin Pharmacol46: 291–300.
88.
MarheRWatersAJvan de WeteringBJ. (2013) Implicit and explicit drug-related cognitions during detoxification treatment are associated with drug relapse: An ecological momentary assessment study. J Consult Clin Psychol81: 1–12.
89.
MathewSJVythilingamMMurroughJW. (2011) A selective neurokinin-1 receptor antagonist in chronic PTSD: A randomized, double-blind, placebo-controlled, proof-of-concept trial. Eur Neuropsychopharmacol21: 221–229.
90.
MitchellJMTavaresVCFieldsHL. (2007) Endogenous opioid blockade and impulsive responding in alcoholics and healthy controls. Neuropsychopharmacology32: 439–449.
91.
MoellerFGKjomeKLMaL (2010a) Imaging advances in developing new medications for addiction. Neuropsychopharmacology35: 339–340.
92.
MoellerFGSteinbergJLSchmitzJM. (2010b) Working memory fMRI activation in cocaine-dependent subjects: Association with treatment response. Psychiatry Res181: 174–182.
93.
MoggKBradleyBPO’NeillB. (2012) Effect of dopamine D(3) receptor antagonism on approach responses to food cues in overweight and obese individuals. Behav Pharmacol23: 603–608.
94.
Morein-ZamirSRobbinsTW (2014) Fronto-striatal circuits in response-inhibition: Relevance to addiction. Brain Res.doi: 10.1016/j.brainres.2014.09.012. [Epub ahead of print].
95.
MugnainiMIavaroneLCavalliniP. (2013) Occupancy of brain dopamine D3 receptors and drug craving: A translational approach. Neuropsychopharmacology38: 302–312.
96.
MurtraPSheasbyAMHuntSP. (2000) Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature405: 180–183.
97.
MyrickHAntonRFLiX. (2008) Effect of naltrexone and ondansetron on alcohol cue-induced activation of the ventral striatum in alcohol-dependent people. Arch Gen Psychiatry65: 466–475.
98.
National Centre for Social Research and Department of Health Sciences (2009) Adult psychiatric morbidity in England, 2007. Results of a household survey. London: NHS Information Centre for Health and Social Care.
99.
National Treatment Agency and Department of Health (2013a) Alcohol statistics from the National Drug Treatment Monitoring System (NDTMS), 1 April 2012 to 31 March 2013. London: Department of Health.
100.
National Treatment Agency and Department of Health (2013b) Drug statistics from the National Drug Treatment Monitoring System (NDTMS), 1 April 2012 to 31 March 2013. London: Department of Health.
101.
NielsenMORostrupEWulffS. (2012) Improvement of brain reward abnormalities by antipsychotic monotherapy in schizophrenia. Arch Gen Psychiatry69: 1195–1204.
102.
NiggJTWongMMMartelMM. (2006) Poor response inhibition as a predictor of problem drinking and illicit drug use in adolescents at risk for alcoholism and other substance use disorders. J Am Acad Child Adolesc Psychiatry45: 468–475.
103.
NoelXBreversDBecharaA (2013) A neurocognitive approach to understanding the neurobiology of addiction. Curr Opin Neurobiol23: 632–638.
104.
OlmsteadMCOuagazzalAMKiefferBL (2009) Mu and delta opioid receptors oppositely regulate motor impulsivity in the signaled nose poke task. PLoS One4: e4410.
105.
OswaldLMWongDFZhouY. (2007) Impulsivity and chronic stress are associated with amphetamine-induced striatal dopamine release. Neuroimage36: 153–166.
106.
PattijTSchettersDJanssenMC. (2009) Acute effects of morphine on distinct forms of impulsive behavior in rats. Psychopharmacology (Berl)205: 489–502.
107.
PayerDEBehzadiAKishSJ. (2014) Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: A positron emission tomography study with [11C]-+-PHNO. Neuropsychopharmacology39: 311–318.
PiazzaPVLe MoalM (1998) The role of stress in drug self-administration. Trends Pharmacol Sci19: 67–74.
110.
PillaMPerachonSSautelF. (1999) Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature400: 371–375.
111.
PrestonKLVahabzadehMSchmittnerJ. (2009) Cocaine craving and use during daily life. Psychopharmacology (Berl)207: 291–301.
112.
RamchandaniVAUmhauJPavonFJ. (2011) A genetic determinant of the striatal dopamine response to alcohol in men. Mol Psychiatry16: 809–817.
113.
RipleyTLGaddCADe FelipeC. (2002) Lack of self-administration and behavioural sensitisation to morphine, but not cocaine, in mice lacking NK1 receptors. Neuropharmacology43: 1258–1268.
114.
RogersRDEverittBJBaldacchinoA. (1999) Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: Evidence for monoaminergic mechanisms. Neuropsychopharmacology20: 322–339.
115.
SajiKIkedaYKimW. (2013) Acute NK(1) receptor antagonist administration affects reward incentive anticipation processing in healthy volunteers. Int J Neuropsychopharmacol16: 1461–1471.
116.
SchankJRKingCESunH. (2014) The role of the neurokinin-1 receptor in stress-induced reinstatement of alcohol and cocaine seeking. Neuropsychopharmacology39: 1093–1101.
117.
SchankJRPickensCLRoweKE. (2011) Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L822429. Psychopharmacology (Berl)218: 111–119.
118.
SchlagenhaufFJuckelGKoslowskiM. (2008) Reward system activation in schizophrenic patients switched from typical neuroleptics to olanzapine. Psychopharmacology (Berl)196: 673–684.
119.
SchouwMLDe RuiterMBKaagAM. (2013) Dopaminergic dysfunction in abstinent dexamphetamine users: Results from a pharmacological fMRI study using a reward anticipation task and a methylphenidate challenge. Drug Alcohol Depend130: 52–60.
120.
SearleGBeaverJDComleyRA. (2010) Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist. Biol Psychiatry68: 392–399.
121.
SegalDMMoraesCTMashDC (1997) Up-regulation of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities. Brain Res Mol Brain Res45: 335–339.
122.
SescousseGCalduXSeguraB. (2013) Processing of primary and secondary rewards: A quantitative meta-analysis and review of human functional neuroimaging studies. Neurosci Biobehav Rev37: 681–696.
123.
SheehanDVLecrubierYSheehanKH. (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry59: S22–S33; quiz 34–57.
124.
SimmondsDJPekarJJMostofskySH (2008) Meta-analysis of Go/No-go tasks demonstrating that fMRI activation associated with response inhibition is task-dependent. Neuropsychologia46: 224–232.
125.
SinhaR (2007) The role of stress in addiction relapse. Curr Psychiatry Rep9: 388–395.
126.
SinhaRLiCS (2007) Imaging stress- and cue-induced drug and alcohol craving: Association with relapse and clinical implications. Drug Alcohol Rev26: 25–31.
127.
SinhaRFoxHCHongKA. (2009) Enhanced negative emotion and alcohol craving, and altered physiological responses following stress and cue exposure in alcohol dependent individuals. Neuropsychopharmacology34: 1198–1208.
128.
SjoerdsZde WitSvan den BrinkW. (2013) Behavioral and neuroimaging evidence for overreliance on habit learning in alcohol-dependent patients. Transl Psychiatry3: e337.
StaleyJKMashDC (1996) Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities. J Neurosci16: 6100–6106.
131.
Te BeekETZoethoutRWBaniMS. (2012) Pharmacokinetics and central nervous system effects of the novel dopamine D3 receptor antagonist GSK598809 and intravenous alcohol infusion at pseudo-steady state. J Psychopharmacol26: 303–314.
132.
ThanosPKKatanaJMAshbyCRJr. (2005) The selective dopamine D3 receptor antagonist SB-277011-A attenuates ethanol consumption in ethanol preferring (P) and non-preferring (NP) rats. Pharmacol Biochem Behav81: 190–197.
133.
Verdejo-GarciaALawrenceAJClarkL (2008) Impulsivity as a vulnerability marker for substance-use disorders: Review of findings from high-risk research, problem gamblers and genetic association studies. Neurosci Biobehav Rev32: 777–810.
134.
VerheulRvan den BrinkWGeerlingsP (1999) A three-pathway psychobiological model of craving for alcohol. Alcohol Alcohol34:197–222.
135.
VolpicelliJRWatsonNTKingAC. (1995) Effect of naltrexone on alcohol ‘high’ in alcoholics. Am J Psychiatry152: 613–615.
136.
WatanabeJSugiuraMSatoK. (2002) The human prefrontal and parietal association cortices are involved in NO-GO performances: An event-related fMRI study. Neuroimage17: 1207–1216.
137.
WatsonBJTaylorLGReidAG. (2013) Investigating expectation and reward in human opioid addiction with [C]raclopride PET. Addict Biol 19: 1032–1040.
138.
WhiteWL (2012) Recovery/remission from substance use disorders: An analysis of reported outcomes in 415 scientific reports, 1868–2011. Philadelphia, PA: Department of Behavioral Health and Intellectual disAbility Services and the Great Lakes Addiction Technology Transfer Center.
139.
WhitefordHADegenhardtLRehmJ. (2013) Global burden of disease attributable to mental and substance use disorders: Findings from the Global Burden of Disease Study 2010. Lancet382: 1575–1586.
140.
WilliamsTMDaglishMRLingford-HughesA. (2007) Brain opioid receptor binding in early abstinence from opioid dependence: Positron emission tomography study. Br J Psychiatry191: 63–69.
141.
WilliamsTMDaviesSJTaylorLG. (2009) Brain opioid receptor binding in early abstinence from alcohol dependence and relationship to craving: An [11C]diprenorphine PET study. Eur Neuropsychopharmacol19: 740–748.
142.
WraseJSchlagenhaufFKienastT. (2007) Dysfunction of reward processing correlates with alcohol craving in detoxified alcoholics. Neuroimage35: 787–794.
