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 alcoholdependent 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.alcoholism | translational studies | dopamine release | in silico analysis | postmortem brain tissue A bout 10% of the total burden of disease in developed countries is caused by alcohol use alone (1). A large proportion of alcohol-related disability results from alcohol addiction. The condition affects more than 12% of the United States population at some point in their lives and is one of the most prevalent psychiatric disorders in Europe (2, 3). The relapsing course of alcoholism is associated with compulsive drinking, loss of control over intake, and emergence of a negative emotional state during abstinence (4). Afflicted individuals go through repeated cycles of alcohol intoxication and withdrawal leading to persistent alterations in brain activity that are hypothesized to drive relapse and compulsive alcohol use even long after detoxification (5).Seminal studies in experimental animals established that alcohol's rewarding properties are associated with increased dopamine (DA) in regions such as the nucleus accumbens (Acb) (6), whereas withdrawal after chronic alcohol use decreases DA neurotransmission (7). In humans, the binding of a DA receptor ligand, typically one for the D2-like receptor subgroup, i.e., [11 C] raclopride, can be monitored by PET. Displacement of the radioligand provides an indirect measure of DA release and has been used to demonstrate alcohol-evoked DA release in...

Region specific activation of the AKT and mTORC1 pathway in response to excessive alcohol intake in rodents

“…As increased glutamatergic excitability is observed during withdrawal periods (Wang et al, 2010), thus it is plausible that glutamatergic signaling contributes to the activation of this pathway in the NAc shell and/or OFC. Interestingly, Hirth et al recently demonstrated a hyperdopaminergic state during protracted abstinence, showing that opposite dynamical changes take place in the mesolimbic dopaminergic system in alcohol acute withdrawal and protracted abstinence (Hirth et al, 2016). It would be of interest to test the activation of AKT/mTORC1 signaling pathway after a longer period of abstinence.…”

Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

“…Individuals with AUDs report a broad range of alcohol consumption, between 0.7g/kg/day and ≥ 3.9g/kg/day (Hietala et al, 1994; Hirth et al, 2016; Volkow et al, 2002; Wang et al, 2016). In addition, while some individuals establish chronic heavy drinking behavior, others maintain chronic, lower levels of consumption, and still others develop binge-drinking patterns.…”

Meta-Analysis Reveals Significant Association of the 3′-UTR VNTR inSLC6A3with Alcohol Dependence

“…Very recently, Hirth et al (2016) showed a strong down-regulation of the D1 receptor- and dopamine transporter-binding sites in postmortem brain samples from human alcoholics. Furthermore, many genetic studies have demonstrated an association of variants in SLC6A3 with addiction-related behaviors (Ma et al, 2015b, van der Zwaluw et al, 2009) and neuropsychiatric disorders (Gill et al, 1997, Cornish et al, 2005).…”