%0 Generic
%A Hirth, Natalie
%D 2017
%F heidok:19682
%K alcoholism, opioid system, dopamine system, human post-mortem analysis, animal model
%R 10.11588/heidok.00019682
%T The endogenous opioid system in alcoholism: Translational studies in humans and rodents
%U https://archiv.ub.uni-heidelberg.de/volltextserver/19682/
%X In most parts of the world, alcohol is consumed for social and recreational reasons. However, the initially controllable use can become compulsive and alcohol dependence develops. Late dependence is characterized by persistent neuroadaptations in various brain neurotransmitter systems, including the endogenous opioid and dopamine system, which are thought to underlie relapse. Many hypotheses on the state of brain neurotransmitter systems are based on positron emission tomography (PET) studies. However, the interpretation of those data is challenging as PET signals are sensitive not only to receptor but also ligand levels. For instance, increased μ-opioid receptor (MOR) PET binding potentials are interpreted as elevated receptor levels. Those are thought to be the target of the anti-relapse medication naltrexone, an opioid antagonist. However, naltrexone’s effect size is relatively small and only a subset of alcohol-dependent patients appears to benefit. Furthermore, only few studies on the opioid and dopamine system during protracted abstinence are available. This is surprising as this phase is characterized by high relapse propensity and, thus, is clinically highly relevant.  Therefore, this thesis aims to demonstrate the state of the opioid and dopamine system during alcohol abstinence. A translational approach was applied by analyzing these systems in four separate studies (Study I-IV) in post-mortem brain tissue of human alcoholics and an animal model of alcohol dependence.  In Study I, transcriptional and protein levels (receptor binding sites) of the MOR are found to be strongly reduced in the striatum of alcoholics. Additionally, a PET study associates decreased striatal MOR binding potential with higher relapse risk. Decreased MOR expression is mirrored by data from alcohol-dependent rats in Study II. Furthermore, the precursor of the MOR-ligand β-endorphin Pomc is significantly reduced. Signaling at the δ-opioid receptor (DOR) appears to be decreased in alcohol dependence while the κ-opioid receptor (KOR) system is upregulated. In Study III, chronic naltrexone treatment counteracts the changes in MOR/Pomc levels by significantly increasing expression and further enhanced KOR density. The DOR, in contrast, seems not to be a target of naltrexone under the applied experimental conditions. Because the endogenous opioid system is known to modulate dopamine release, the dopamine system was investigated in Study IV. Here, human post-mortem tissue reveals strongly decreased dopamine transporter and D1 receptor levels in alcoholics while D2 is unchanged. These findings are further supported by the alcohol-dependent animals where an oscillatory-like regulation of the dopamine system is observed during acute withdrawal and protracted abstinence. While previous studies report on a hypodopaminergic state during acute withdrawal, here, a hyperdopaminergic state is demonstrated during protracted abstinence by measurements of striatal dopamine release and a meta-analysis followed by functional validations. Based on these data, both hypo- and hyperdopaminergic states are suggested as phases with increased vulnerability for alcohol relapse. In summary, the results presented in this thesis provide consistent evidence for a severe dysregulation of the endogenous opioid and dopamine system during alcohol abstinence that demands reinterpretation of existing PET data. It is proposed for future studies to combine the analysis of human post-mortem tissue and established animal models with PET studies to achieve a more precise picture of the state of brain neurotransmitter systems in alcoholic patients. Moreover, decreased MOR and dopamine receptor/transporter levels may represent molecular markers of the disease course that can be used to develop personalized treatment approaches.