Convergent studies on neurotransmitter adaptations in brain tissues of alcohol dependent rats and human alcoholics

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Natalie Hirth, Hamid R Noori, Valentina Vengeliene, Georg Köhr, Wolfgang H Sommer, Rainer Spanagel, Anita C Hansson
Institute of Psychopharmacology, Central Institute of Mental Health Mannheim, Medical Faculty of Mannheim, Heidelberg University, Mannheim, DE

Dependence is characterized by persistent neuroadaptations in various brain neurotransmitter systems, including the endogenous opioid and dopamine system, which are thought to underlie relapse. A major hypothesis in the addiction field suggests deficits in dopamine signaling during abstinence. This hypodopaminergic state is seen as a driving mechanism for the relapsing course of the disorder. Experimental support for this view comes mostly from human positron emission tomography (PET) studies that found reduced striatal D2-like receptor binding potential in alcoholics. However, the interpretation of those data is challenging as PET signals are sensitive not only to receptor but also endogenous ligand levels. Here we systematically study neuroadaptive changes in the DA system during the addiction cycle in alcohol dependent patients and rats. In post-mortem brain samples from human alcoholics we found a strong downregulation of D1 receptor and dopamine transporter (DAT) binding sites, while D2-like receptor binding was unaffected. To gain insight into the time course of these neuroadaptations we compared the human data to alcohol dependent rats at several time points during abstinence and found a dynamic regulation of D1 and DAT during three weeks 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. Functional evidence is further given by a genetic rat model for hyperdopaminergia that resembles a phenocopy of dependent rats during protracted abstinence. In summary, we provide a new dynamic model of abstinence-related changes of the striatal DA system in which a hyperdopaminergic state during protracted abstinence is associated with vulnerability for relapse.