Neurochemical and metabolic effects of acute and chronic alcohol in the human brain: Studies with positron emission tomography

The use of Positron emission tomography (PET) to study the effects of acute and chronic alcohol on the human brain has enhanced our understanding of the mechanisms underlying alcohol's rewarding effects, the neuroadaptations from chronic exposure that contribute to tolerance and withdrawal, and the changes in fronto-striatal circuits that lead to loss of control and enhanced motivation to drink that characterize alcohol use disorders (AUD). These include studies showing that alcohol's reinforcing effects may result not only from its enhancement of dopaminergic, GABAergic and opioid signaling but also from its caloric properties. Studies in those suffering from an AUD have revealed significant alterations in dopamine (DA), GABA, cannabinoids, opioid and serotonin neurotransmission and in brain energy utilization (glucose and acetate metabolism) that are likely to contribute to compulsive alcohol taking, dysphoria/depression, and to alcohol-associated neurotoxicity. Studies have also evaluated the effects of abstinence on recovery of brain metabolism and neurotransmitter function and the potential value of some of these measures to predict clinical outcomes. Finally, PET studies have started to provide insights about the neuronal mechanisms by which certain genes contribute to the vulnerability to AUD. These findings have helped identify new strategies for prevention and treatment of AUD. This article is part of the Special Issue entitled "Alcoholism".

[1]  Robert B. Innis,et al.  Cortical γ-aminobutyric acid type A-benzodiazepine receptors in recovery from alcohol dependence : Relationship to features of alcohol dependence and cigarette smoking , 2005 .

[2]  M. Nicolelis,et al.  Intravascular Food Reward , 2011, PloS one.

[3]  D. Nutt,et al.  Brain opioid receptor binding in early abstinence from alcohol dependence and relationship to craving: An [11C]diprenorphine PET study , 2009, European Neuropsychopharmacology.

[4]  Jenna M. Sullivan,et al.  Limitations of SRTM, Logan graphical method, and equilibrium analysis for measuring transient dopamine release with [(11)C]raclopride PET. , 2013, American journal of nuclear medicine and molecular imaging.

[5]  Garth E. Terry,et al.  Reduced cannabinoid CB1 receptor binding in alcohol dependence measured with positron emission tomography , 2013, Molecular Psychiatry.

[6]  D. Werner,et al.  The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress , 2009, Psychopharmacology.

[7]  A. Michalak,et al.  ALCOHOL DEPENDENCE--NEUROBIOLOGY AND TREATMENT. , 2016, Acta poloniae pharmaceutica.

[8]  Alexander Hammers,et al.  Acute increases in synaptic GABA detectable in the living human brain: A [11C]Ro15-4513 PET study , 2014, NeuroImage.

[9]  A. Lingford-Hughes,et al.  Levels of gamma-aminobutyric acid-benzodiazepine receptors in abstinent, alcohol-dependent women: preliminary findings from an 123I-iomazenil single photon emission tomography study. , 2000, Alcoholism, clinical and experimental research.

[10]  Siegfried Kasper,et al.  Normative database of the serotonergic system in healthy subjects using multi-tracer PET , 2012, NeuroImage.

[11]  Nora D. Volkow,et al.  Low doses of alcohol substantially decrease glucose metabolism in the human brain , 2006, NeuroImage.

[12]  Christer Halldin,et al.  Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain. , 2013, The international journal of neuropsychopharmacology.

[13]  R. C. Pierce,et al.  The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse? , 2006, Neuroscience & Biobehavioral Reviews.

[14]  C. Gianoulakis Endogenous opioids and addiction to alcohol and other drugs of abuse. , 2009, Current topics in medicinal chemistry.

[15]  J. Fernández-Ruiz,et al.  Altered CB1 receptor coupling to G-proteins in the post-mortem caudate nucleus and cerebellum of alcoholic subjects , 2015, Journal of psychopharmacology.

[16]  Christer Halldin,et al.  Application of cross-species PET imaging to assess neurotransmitter release in brain , 2015, Psychopharmacology.

[17]  D. Wong,et al.  Family history of alcoholism is related to increased D2/D3 receptor binding potential: a marker of resilience or risk? , 2017, Addiction biology.

[18]  William J Jagust,et al.  Alcohol Consumption Induces Endogenous Opioid Release in the Human Orbitofrontal Cortex and Nucleus Accumbens , 2012, Science Translational Medicine.

[19]  P. Groves,et al.  Burst firing induced in midbrain dopamine neurons by stimulation of the medial prefrontal and anterior cingulate cortices , 1988, Brain Research.

[20]  Ulla Ruotsalainen,et al.  A PET Study on the Acute Effect of Ethanol on Striatal D2 Dopamine Receptors with [11C]Raclopride in Healthy Males , 1997 .

[21]  R. Constable,et al.  Disrupted ventromedial prefrontal function, alcohol craving, and subsequent relapse risk. , 2013, JAMA psychiatry.

[22]  N. Volkow,et al.  BMI Modulates Calorie-Dependent Dopamine Changes in Accumbens from Glucose Intake , 2014, PloS one.

[23]  Masami Nishikawa,et al.  Alterations in brain serotonin synthesis in male alcoholics measured using positron emission tomography. , 2009, Alcoholism, clinical and experimental research.

[24]  N. Volkow,et al.  Addiction: Beyond dopamine reward circuitry , 2011, Proceedings of the National Academy of Sciences.

[25]  David Weinzimmer,et al.  Cortical gamma-aminobutyric acid type A-benzodiazepine receptors in recovery from alcohol dependence: relationship to features of alcohol dependence and cigarette smoking. , 2005, Archives of general psychiatry.

[26]  Jari Tiihonen,et al.  Dopamine transporter availability and depressive symptoms during alcohol withdrawal , 1999, Psychiatry Research: Neuroimaging.

[27]  F. A. Schroeder,et al.  A Novel Radiotracer for Imaging Monoacylglycerol Lipase in the Brain Using Positron Emission Tomography. , 2016, ACS chemical neuroscience.

[28]  J. Virkkala,et al.  Intravenous Ethanol Increases Dopamine Release in the Ventral Striatum in Humans: PET Study Using Bolus-Plus-Infusion Administration of [11C]raclopride , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[29]  N. Volkow,et al.  PET imaging for addiction medicine: From neural mechanisms to clinical considerations. , 2016, Progress in brain research.

[30]  Mariya V. Cherkasova,et al.  Reduced Dopamine Response to Amphetamine in Subjects at Ultra-High Risk for Addiction , 2014, Biological Psychiatry.

[31]  A. Batra,et al.  Low μ-Opioid Receptor Status in Alcohol Dependence Identified by Combined Positron Emission Tomography and Post-Mortem Brain Analysis , 2017, Neuropsychopharmacology.

[32]  H. Kranzler,et al.  GABRA2 Alcohol Dependence Risk Allele is Associated with Reduced Expression of Chromosome 4p12 GABAA Subunit Genes in Human Neural Cultures. , 2015, Alcoholism, clinical and experimental research.

[33]  A. Dagher,et al.  Alcohol promotes dopamine release in the human nucleus accumbens , 2003, Synapse.

[34]  Mark Slifstein,et al.  Alcohol Dependence Is Associated with Blunted Dopamine Transmission in the Ventral Striatum , 2005, Biological Psychiatry.

[35]  G. Chiara Nucleus accumbens shell and core dopamine: differential role in behavior and addiction , 2002, Behavioural Brain Research.

[36]  Karmen K. Yoder,et al.  Dopamine D(2) receptor availability is associated with subjective responses to alcohol. , 2005, Alcoholism, clinical and experimental research.

[37]  N. Volkow,et al.  Regional brain metabolic response to lorazepam in subjects at risk for alcoholism. , 1995, Alcoholism, clinical and experimental research.

[38]  N. Volkow,et al.  Brain imaging biomarkers to predict relapse in alcohol addiction. , 2013, JAMA psychiatry.

[39]  D. Ingvar,et al.  Acute effects of alcohol on regional cerebral blood flow in man. , 1993, Journal of studies on alcohol.

[40]  Mario Dzemidzic,et al.  Beer Flavor Provokes Striatal Dopamine Release in Male Drinkers: Mediation by Family History of Alcoholism , 2013, Neuropsychopharmacology.

[41]  D. Hommer,et al.  Effects of m-Chlorophenylpiperazine on Regional Brain Glucose Utilization: A Positron Emission Tomographic Comparison of Alcoholic and Control Subjects , 1997, The Journal of Neuroscience.

[42]  Theresa H. McKim,et al.  Translational Research on Habit and Alcohol , 2016, Current Addiction Reports.

[43]  M Laruelle,et al.  Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil. , 1998, The American journal of psychiatry.

[44]  A. Reilhac,et al.  [18F]fallypride PET measurement of striatal and extrastriatal dopamine D2/3 receptor availability in recently abstinent alcoholics , 2010, Addiction biology.

[45]  Mark Slifstein,et al.  Positron Emission Tomography Imaging of the Serotonin Transporter and 5-HT1A Receptor in Alcohol Dependence , 2009, Biological Psychiatry.

[46]  C. Heyser,et al.  mu-Opioid receptor knockout mice do not self-administer alcohol. , 2000, The Journal of pharmacology and experimental therapeutics.

[47]  Mario Dzemidzic,et al.  Beer self-administration provokes lateralized nucleus accumbens dopamine release in male heavy drinkers , 2014, Psychopharmacology.

[48]  Jari Karhu,et al.  Altered striatal dopamine re-uptake site densities in habitually violent and non-violent alcoholics , 1995, Nature Medicine.

[49]  Yiyun Huang,et al.  Positron emission tomography shows elevated cannabinoid CB1 receptor binding in men with alcohol dependence. , 2012, Alcoholism, clinical and experimental research.

[50]  J. Volpicelli,et al.  A comparison of the effects of the opioid antagonists naltrexone, naltrindole, and beta-funaltrexamine on ethanol consumption in the rat. , 1998, Alcohol.

[51]  P W Woodruff,et al.  Reduced levels of GABA-benzodiazepine receptor in alcohol dependency in the absence of grey matter atrophy , 1998, British Journal of Psychiatry.

[52]  N. Volkow,et al.  Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study , 2002, Psychiatry Research: Neuroimaging.

[53]  P. Hyytiä,et al.  Responding for oral ethanol after naloxone treatment by alcohol-preferring AA rats. , 1993, Alcoholism, clinical and experimental research.

[54]  J S Fowler,et al.  Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. , 1999, The American journal of psychiatry.

[55]  James W. Walters,et al.  Differences in IV alcohol-induced dopamine release in the ventral striatum of social drinkers and nontreatment-seeking alcoholics. , 2016, Drug and alcohol dependence.

[56]  R. Narendran,et al.  Dopamine D1 receptors in cocaine dependence measured with PET and the choice to self-administer cocaine , 2009, Neuropsychopharmacology.

[57]  N. Volkow,et al.  Decreased dopamine activity predicts relapse in methamphetamine abusers , 2011, Molecular Psychiatry.

[58]  J. Oikawa,et al.  Effects of acute ethanol administration on methionine–enkephalin expression and release in regions of the rat brain , 2010, Neuropeptides.

[59]  J. Heikkilä,et al.  Dopamine transporters increase in human brain after alcohol withdrawal , 1999, Molecular Psychiatry.

[60]  L. Callado,et al.  Involvement of the endocannabinoid system in alcohol dependence: the biochemical, behavioral and genetic evidence. , 2011, Drug and alcohol dependence.

[61]  Jean Logan,et al.  Brain DA D2 receptors predict reinforcing effects of stimulants in humans: Replication study , 2002, Synapse.

[62]  Nora D. Volkow,et al.  Positive Emotionality is Associated with Baseline Metabolism in Orbitofrontal Cortex and in Regions of the Default Network , 2011, Molecular Psychiatry.

[63]  Mathias Schreckenberger,et al.  Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving. , 2004, The American journal of psychiatry.

[64]  L. Lumeng,et al.  Importance of delta opioid receptors in maintaining high alcohol drinking , 1991, Psychopharmacology.

[65]  Zsolt Szabo,et al.  Positron emission tomography imaging of the serotonin transporter in subjects with a history of alcoholism , 2004, Biological Psychiatry.

[66]  P. Janak,et al.  Habitual Alcohol Seeking: Neural Bases and Possible Relations to Alcohol Use Disorders. , 2016, Alcoholism, clinical and experimental research.

[67]  Karmen K. Yoder,et al.  Monetary discounting and ventral striatal dopamine receptor availability in nontreatment-seeking alcoholics and social drinkers , 2015, Psychopharmacology.

[68]  N. Volkow,et al.  Therapeutic doses of buspirone block D3 receptors in the living primate brain. , 2014, The international journal of neuropsychopharmacology.

[69]  Laurent Descarries,et al.  Decreased [18F]MPPF Binding Potential in the Dorsal Raphe Nucleus After a Single Oral Dose of Fluoxetine: A Positron-Emission Tomography Study in Healthy Volunteers , 2008, Biological Psychiatry.

[70]  Frode Willoch,et al.  Imaging of opioid receptors in the central nervous system , 2007, Brain : a journal of neurology.

[71]  N. Volkow,et al.  Predominance of D2 Receptors in Mediating Dopamine's Effects in Brain Metabolism: Effects of Alcoholism , 2013, The Journal of Neuroscience.

[72]  S. Galiègue,et al.  Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. , 1995, European journal of biochemistry.

[73]  F. Turkheimer,et al.  Measuring endogenous changes in serotonergic neurotransmission in humans: a [11C]CUMI-101 PET challenge study , 2012, Molecular Psychiatry.

[74]  J. Tiihonen,et al.  Striatal presynaptic dopamine function in type 1 alcoholics measured with positron emission tomography , 1998, Molecular Psychiatry.

[75]  R. Lydiard The role of GABA in anxiety disorders. , 2003, The Journal of clinical psychiatry.

[76]  J. Krystal,et al.  Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[77]  N. Volkow,et al.  Alcohol Decreases Baseline Brain Glucose Metabolism More in Heavy Drinkers Than Controls But Has No Effect on Stimulation-Induced Metabolic Increases , 2015, The Journal of Neuroscience.

[78]  Sid Gilman,et al.  Positron emission tomographic studies of cerebral benzodiazepine‐receptor binding in chronic alcoholics , 1996, Annals of neurology.

[79]  Hiroto Kuwabara,et al.  Striatal dopamine release and family history of alcoholism. , 2006, Alcoholism, clinical and experimental research.

[80]  Mark Slifstein,et al.  Sex Differences in Striatal Dopamine Release in Young Adults After Oral Alcohol Challenge: A Positron Emission Tomography Imaging Study With [11C]Raclopride , 2010, Biological Psychiatry.

[81]  Fumitoshi Kodaka,et al.  Serotonergic neurotransmission in the living human brain: A positron emission tomography study using [11C]dasb and [11C]WAY100635 in young healthy men , 2011, Synapse.

[82]  K. Ma,et al.  Availability of the serotonin transporter in patients with alcohol dependence , 2011, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[83]  Nora D Volkow,et al.  Neurocircuitry of Addiction , 2010, Neuropsychopharmacology.

[84]  M. Schuckit,et al.  The search for genes contributing to the low level of response to alcohol: patterns of findings across studies. , 2004, Alcoholism, clinical and experimental research.

[85]  Nora D. Volkow,et al.  Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement , 2007, The Journal of Neuroscience.

[86]  N. Volkow,et al.  NOW vs LATER brain circuits: implications for obesity and addiction , 2015, Trends in Neurosciences.

[87]  John H Krystal,et al.  Increased brain uptake and oxidation of acetate in heavy drinkers. , 2013, The Journal of clinical investigation.

[88]  G. Koob Drugs of abuse: anatomy, pharmacology and function of reward pathways. , 1992, Trends in pharmacological sciences.

[89]  M. Le Moal,et al.  Neurobiological mechanisms for opponent motivational processes in addiction , 2008, Philosophical Transactions of the Royal Society B: Biological Sciences.

[90]  Marios Politis,et al.  Neuroimaging in Parkinson disease: from research setting to clinical practice , 2014, Nature Reviews Neurology.

[91]  Nora D. Volkow,et al.  The Brain on Drugs: From Reward to Addiction , 2015, Cell.

[92]  D. Hommer,et al.  A genetic determinant of the striatal dopamine response to alcohol in men , 2010, Molecular Psychiatry.

[93]  Alexander Hammers,et al.  A [11C]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced α5 benzodiazepine receptors in limbic regions , 2012, Journal of psychopharmacology.

[94]  J. Heikkilä,et al.  SPECT scans showing recovery of dopamine transporters in human brain after alcohol withdrawal , 1999, Molecular Psychiatry.

[95]  Ulla Ruotsalainen,et al.  Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence , 1994, Psychopharmacology.

[96]  Koen Van Laere,et al.  Whole-Body Biodistribution and Radiation Dosimetry of the Cannabinoid Type 2 Receptor Ligand [11C]-NE40 in Healthy Subjects , 2011, Molecular Imaging and Biology.

[97]  D. Nutt,et al.  In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism , 2014, Neuropsychopharmacology.

[98]  Yiyun Huang,et al.  Serotonin 1B Receptor Imaging in Alcohol Dependence , 2009, Biological Psychiatry.

[99]  R. Nicoll,et al.  Endocannabinoid Signaling in the Brain , 2002, Science.

[100]  H Ronald Zielke,et al.  Activation of astrocytes in brain of conscious rats during acoustic stimulation: acetate utilization in working brain , 2005, Journal of neurochemistry.

[101]  Paul Cumming,et al.  Correlation of alcohol craving with striatal dopamine synthesis capacity and D2/3 receptor availability: a combined [18F]DOPA and [18F]DMFP PET study in detoxified alcoholic patients. , 2005, The American journal of psychiatry.

[102]  J. Trudell,et al.  Alcohol dependence: molecular and behavioral evidence. , 2014, Trends in pharmacological sciences.

[103]  J. Litton,et al.  Reduced [11C]flumazenil radioligand binding in the thalamus in alcoholics , 2000, Addiction biology.

[104]  A. Feeney,et al.  GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study , 2005, Psychopharmacology.

[105]  R. A. Waniewski,et al.  Preferential Utilization of Acetate by Astrocytes Is Attributable to Transport , 1998, The Journal of Neuroscience.

[106]  N. Volkow,et al.  Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers , 2014, Molecular Psychiatry.

[107]  J. Hirvonen In vivo imaging of the cannabinoid CB1 receptor with positron emission tomography , 2015, Clinical pharmacology and therapeutics.

[108]  A. R. Lang,et al.  Expectations of alcohol-induced positive affect: a cross-cultural comparison. , 2000, Journal of studies on alcohol.

[109]  S. Gilman,et al.  Decreased striatal monoaminergic terminals in severe chronic alcoholism demonstrated with (+)[11C]Dihydrotetrabenazine and positron emission tomography , 1998, Annals of neurology.

[110]  N. Volkow,et al.  Neurobiologic Advances from the Brain Disease Model of Addiction. , 2016, The New England journal of medicine.

[111]  John D. Beaver,et al.  Imaging Dopamine D3 Receptors in the Human Brain with Positron Emission Tomography, [11C]PHNO, and a Selective D3 Receptor Antagonist , 2010, Biological Psychiatry.

[112]  J. Frost,et al.  Mu-opioid receptor binding measured by [11C]carfentanil positron emission tomography is related to craving and mood in alcohol dependence , 2004, Biological Psychiatry.

[113]  Jan-Eric Litton,et al.  PET analysis of [11C]flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls , 1993, Psychiatry Research: Neuroimaging.

[114]  D. Stein,et al.  Pharmacotherapy for anxiety and comorbid alcohol use disorders. , 2015, The Cochrane database of systematic reviews.

[115]  M. Salaspuro,et al.  Increased blood acetate: a new laboratory marker of alcoholism and heavy drinking. , 1985, Alcoholism, clinical and experimental research.

[116]  L. D. Reid,et al.  Morphine and naloxone modulate intake of ethanol. , 1984, Alcohol.

[117]  L. Parsons,et al.  Endocannabinoid signalling in reward and addiction , 2015, Nature Reviews Neuroscience.

[118]  C. Ledent,et al.  Decreased alcohol self-administration and increased alcohol sensitivity and withdrawal in CB1 receptor knockout mice , 2004, Neuropharmacology.

[119]  Nora D. Volkow,et al.  Acute alcohol intoxication decreases glucose metabolism but increases acetate uptake in the human brain , 2013, NeuroImage.

[120]  James M. Bjork,et al.  The effects of acute alcohol administration on the human brain: Insights from neuroimaging , 2014, Neuropharmacology.

[121]  H. Begleiter,et al.  What is inherited in the predisposition toward alcoholism? A proposed model. , 1999, Alcoholism, clinical and experimental research.

[122]  Shiu-Nan Chen,et al.  Apoptotic cell: linkage of inflammation and wound healing , 2014, Front. Pharmacol..

[123]  J S Fowler,et al.  Regional brain metabolic response to lorazepam in alcoholics during early and late alcohol detoxification. , 1997, Alcoholism, clinical and experimental research.

[124]  C. Pilapil,et al.  Mu opioid receptor binding sites in human brain. , 1986, NIDA research monograph.

[125]  J. Pikkarainen,et al.  Increased serum acetate as a marker of problem drinking among drunken drivers. , 1988, Alcohol and alcoholism.

[126]  Garret D Stuber,et al.  Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release , 2015, Journal of neurochemistry.

[127]  C. Heyser,et al.  Neurocircuitry targets in ethanol reward and dependence. , 1998, Alcoholism, clinical and experimental research.

[128]  G. Koob,et al.  The sequenced rat brain transcriptome – its use in identifying networks predisposing alcohol consumption , 2015, The FEBS journal.

[129]  J S Fowler,et al.  Decreases in dopamine receptors but not in dopamine transporters in alcoholics. , 1996, Alcoholism, clinical and experimental research.

[130]  Alan A. Wilson,et al.  The Fatty Acid Amide Hydrolase C385A Variant Affects Brain Binding of the Positron Emission Tomography Tracer [11C]CURB , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[131]  S. J. Gatley,et al.  Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects , 1997, Nature.

[132]  P. Janak,et al.  Habitual Alcohol Seeking: Time Course and the Contribution of Subregions of the Dorsal Striatum , 2012, Biological Psychiatry.

[133]  A. Heinz,et al.  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. , 2005, Archives of general psychiatry.

[134]  N. Volkow,et al.  Monoamine oxidase: radiotracer chemistry and human studies. , 2015, Journal of labelled compounds & radiopharmaceuticals.

[135]  Hiroto Kuwabara,et al.  Positron emission tomography imaging of mu- and delta-opioid receptor binding in alcohol-dependent and healthy control subjects. , 2011, Alcoholism, clinical and experimental research.

[136]  T. Robbins,et al.  Behavioral and neuroimaging evidence for overreliance on habit learning in alcohol-dependent patients , 2013, Translational Psychiatry.

[137]  Alan A. Wilson,et al.  Recent methods for measuring dopamine D3 receptor occupancy in vivo: importance for drug development , 2014, Front. Pharmacol..

[138]  G. Gessa,et al.  Alcohol withdrawal in rats is associated with a marked fall in extraneuronal dopamine. , 1992, Alcoholism, clinical and experimental research.

[139]  R. Anton Naltrexone for the management of alcohol dependence. , 2008, The New England journal of medicine.

[140]  Joshua A. Bueller,et al.  Regional Mu Opioid Receptor Regulation of Sensory and Affective Dimensions of Pain , 2001, Science.

[141]  Frank Telang,et al.  High levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factors. , 2006, Archives of general psychiatry.

[142]  Steven H. Liang,et al.  Synthesis and Preliminary PET Imaging Studies of a FAAH Radiotracer ([¹¹C]MPPO) Based on α-Ketoheterocyclic Scaffold. , 2016, ACS chemical neuroscience.

[143]  A. Abi-Dargham,et al.  Molecular imaging in alcohol dependence. , 2014, Handbook of clinical neurology.

[144]  R. Drake,et al.  Family History of Alcoholism in Schizophrenia , 1994, The Journal of nervous and mental disease.

[145]  N. Volkow,et al.  Decreased cerebral response to inhibitory neurotransmission in alcoholics. , 1993, The American journal of psychiatry.

[146]  M J Eckardt,et al.  Effects of moderate alcohol consumption on the central nervous system. , 1998, Alcoholism: Clinical and Experimental Research.

[147]  Jeih-San Liow,et al.  PET [11C]DASB imaging of serotonin transporters in patients with alcoholism. , 2007, Alcoholism, clinical and experimental research.

[148]  L. Nyberg,et al.  Dopamine D1 Binding Potential Predicts Fusiform BOLD Activity during Face-Recognition Performance , 2015, The Journal of Neuroscience.

[149]  Garth E. Terry,et al.  Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers , 2012, Molecular Psychiatry.

[150]  N. Volkow,et al.  Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications , 2011, Nature Reviews Neuroscience.

[151]  R Coppola,et al.  Reduced central serotonin transporters in alcoholism. , 1998, The American journal of psychiatry.

[152]  F. Gonon,et al.  Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo , 1993, Neuroscience Letters.

[153]  G. Koob,et al.  Increased ethanol self-administration in delta-opioid receptor knockout mice. , 2001, Alcoholism, clinical and experimental research.

[154]  R. Kessler,et al.  Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. , 1997, Archives of general psychiatry.

[155]  Jean Logan,et al.  Imaging endogenous dopamine competition with [11C]raclopride in the human brain , 1994, Synapse.

[156]  D L Rothman,et al.  Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients. , 1999, The American journal of psychiatry.

[157]  A. Dahan,et al.  Functional biomarkers for the acute effects of alcohol on the central nervous system in healthy volunteers. , 2011, British journal of clinical pharmacology.

[158]  Andreas Heinz,et al.  A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity , 2000, Biological Psychiatry.

[159]  T. Owonikoko,et al.  Positron Emission Tomography Imaging of the Serotonin Transporter in Subjects with a History of , 2004 .

[160]  G. Koob,et al.  Increased Ethanol Self‐Administration in δ‐Opioid Receptor Knockout Mice , 2001 .

[161]  D. Newlin,et al.  Effect of alcohol ingestion on regional cerebral blood flow. , 1982, The International journal of neuroscience.

[162]  A. Heinz,et al.  Increased Turnover of Dopamine in Caudate Nucleus of Detoxified Alcoholic Patients , 2013, PloS one.

[163]  A. Roberts,et al.  Neurobiological Signatures of Alcohol Dependence Revealed by Protein Profiling , 2013, PloS one.

[164]  Nora D. Volkow,et al.  Effects of acute alcohol intoxication on cerebral blood flow measured with PET , 1988, Psychiatry Research.

[165]  P. Hyytiä,et al.  Suppression of ethanol responding by centrally administered CTOP and naltrindole in AA and Wistar rats. , 2001, Alcoholism, clinical and experimental research.

[166]  V. Dhawan,et al.  Positron emission tomography imaging. , 2009, Frontiers of neurology and neuroscience.

[167]  Douglas W. Jones,et al.  Genotype Influences In Vivo Dopamine Transporter Availability in Human Striatum , 2000, Neuropsychopharmacology.

[168]  Jari Karhu,et al.  Dopamine transporter and D2-receptor density in late-onset alcoholism , 1999, Psychopharmacology.

[169]  N. Volkow,et al.  Acute effects of ethanol on regional brain glucose metabolism and transport , 1990, Psychiatry Research: Neuroimaging.

[170]  S. Gilman,et al.  Effects of disulfiram on positron emission tomography and neuropsychological studies in severe chronic alcoholism. , 1996, Alcoholism, clinical and experimental research.