title: Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence.
abstract: A major hypothesis in addiction research is that alcohol induces neuroadaptations in the mesolimbic dopamine (DA) system and that these neuroadaptations represent a key neurochemical event in compulsive drug use and relapse. Whether these neuroadaptations lead to a hypo- or hyperdopaminergic state during abstinence is a long-standing, unresolved debate among addiction researchers. The answer is of critical importance for understanding the neurobiological mechanism of addictive behavior. Here we set out to study systematically the neuroadaptive changes in the DA system during the addiction cycle in alcohol-dependent patients and rats. In postmortem brain samples from human alcoholics we found a strong down-regulation of the D1 receptor- and DA transporter (DAT)-binding sites, but D2-like receptor binding was unaffected. To gain insight into the time course of these neuroadaptations, we compared the human data with that from alcohol-dependent rats at several time points during abstinence. We found a dynamic regulation of D1 and DAT during 3 wk of abstinence. After the third week the rat data mirrored our human data. This time point was characterized by elevated extracellular DA levels, lack of synaptic response to D1 stimulation, and augmented motor activity. Further functional evidence is given by a genetic rat model for hyperdopaminergia that resembles a phenocopy of alcohol-dependent rats during protracted abstinence. In summary, we provide a new dynamic model of abstinence-related changes in the striatal DA system; in this model a hyperdopaminergic state during protracted abstinence is associated with vulnerability for relapse.
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors.forename: Natalie
authors.initials: N
authors.lastname: Hirth
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Meinhardt
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Noori
authors.affiliation: Neurosciences Department, Autonomous University of Yucatán, 97000 Merida, Yucatan, Mexico;
authors.forename: Humberto
authors.initials: H
authors.lastname: Salgado
authors.affiliation: Neurosciences Department, Autonomous University of Yucatán, 97000 Merida, Yucatan, Mexico;
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Torres-Ramirez
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Uhrig
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors.forename: Laura
authors.initials: L
authors.lastname: Broccoli
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors.forename: Valentina
authors.initials: V
authors.lastname: Vengeliene
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Roßmanith
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Perreau-Lenz
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Köhr
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany; Department of Addictive Behavior and Addiction Medicine at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Sommer
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany;
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany; anita.hansson@zi-mannheim.de.
authors.forename: Anita C
authors.initials: AC
authors.lastname: Hansson
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000328:Adult; D000368:Aged; D064829:Alcohol Abstinence; D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001923:Brain Chemistry; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects* / Q000633:toxicity; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006719:Homovanillic Acid / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D001552:Benzazepines; C581293:DRD2 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D015102:3,4-Dihydroxyphenylacetic Acid; D000431:Ethanol; C067113:SK&F 81297; D004298:Dopamine; D006719:Homovanillic Acid
keywords: alcoholism; dopamine release; in silico analysis; postmortem brain tissue; translational studies