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  Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence

Hirth, N., Meinhardt, M., Noori, H., Salgado, H., Torres-Ramirez, O., Uhrig, S., et al. (2016). Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence. Proceedings of the National Academy of Sciences of the United States of America, 113(11), 3024-3029. doi:10.1073/pnas.1506012113.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-79FC-D Version Permalink: http://hdl.handle.net/21.11116/0000-0000-C881-C
Genre: Journal Article

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Hirth, N, Author
Meinhardt, MW, Author
Noori, HR1, Author              
Salgado, H, Author
Torres-Ramirez, O, Author
Uhrig, S, Author
Broccoli, L, Author
Vengeliene, V, Author
Rossmanith, M, Author
Perreau-Lenz, S, Author
Köhr, G, Author
Sommer, WH, Author
Spanagel, R, Author
Hansson, AC, Author
Affiliations:
1Institute for Psychopharmacology at Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, ou_persistent22              

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 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.

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 Dates: 2016-03
 Publication Status: Published in print
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 Identifiers: DOI: 10.1073/pnas.1506012113
BibTex Citekey: HirthMNSTUBVRPKSSH2016
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Title: Proceedings of the National Academy of Sciences of the United States of America
Source Genre: Journal
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Pages: - Volume / Issue: 113 (11) Sequence Number: - Start / End Page: 3024 - 3029 Identifier: -