Anita Hansson

Dopamine and opioid system adaptation in alcohol addiction

Alcohol potently induces neuroadaptations that promote its incentive salience, escalation of its intake and aversion-resistant alcohol seeking. Such behaviors, which lead to alcohol addiction, are characterized by persistent neuroadaptations in various brain neurotransmitter systems, including the endogenous opioid-, dopamine- and other neuropeptide 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 opioid and dopamine system during the addiction cycle in alcohol dependent patients and rats. 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 highly dynamic regulation of the dopamine system during three weeks of abstinence. Functional evidence is further given by electrophysiology and use of advanced transgenic animal models. In summary, we provide a new dynamic model of abstinence related changes of the striatal dopamine system in which a hyperdopaminergic state during protracted abstinence is associated with vulnerability for relapse. These findings have important implications for our understanding of the pathophysiological mechanisms underlying alcoholism and the interpretation of PET results on dopamine/opioid receptor function in general.