Despite the generally held view that alcohol is an unspecific pharmacological agent, recent molecular pharmacology studies demonstrated that alcohol has only a few known primary targets. These are the NMDA, GABA A , glycine, 5-hydroxytryptamine 3 (serotonin) and nicotinic ACh receptors as well as L-type Ca 2 þ channels and G-protein-activated inwardly rectifying K þ channels. Following this first hit of alcohol on specific targets in the brain, a second wave of indirect effects on a variety of neurotransmitter/neuropeptide systems is initiated that leads subsequently to the typical acute behavioural effects of alcohol, ranging from disinhibition to sedation and even hypnosis, with increasing concentrations of alcohol. Besides these acute pharmacodynamic aspects of alcohol, we discuss the neurochemical substrates that are involved in the initiation and maintenance phase of an alcohol drinking behaviour. Finally, addictive behaviour towards alcohol as measured by alcoholseeking and relapse behaviour is reviewed in the context of specific neurotransmitter/neuropeptide systems and their signalling pathways. The activity of the mesolimbic dopaminergic system plays a crucial role during the initiation phase of alcohol consumption. Following long-term, chronic alcohol consumption virtually all brain neurotransmission seems to be affected, making it difficult to define which of the systems contributes the most to the transition from controlled to compulsive alcohol use. However, compulsive alcohol drinking is characterized by a decrease in the function of the reward neurocircuitry and a recruitment of antireward/stress mechanisms comes into place, with a hypertrophic corticotropin-releasing factor system and a hyperfunctional glutamatergic system being the most important ones.

Loss of control over drinking is a key deficit in alcoholism causally associated with malfunction of the medial prefrontal cortex (mPFC), but underlying molecular and cellular mechanisms remain unclear. Cue-induced reinstatement of alcohol seeking activates a subset of mPFC neurons in rats, identified by their common expression of the activity marker cFos and comprised of both principal and interneurons. Here, we used cFos-lacZ and pCAG-lacZ transgenic rats for activity-dependent or nonselective inactivation of neurons, respectively, which by their lacZ encoded ␤-galactosidase activity convert the inactive prodrug Daun02 into the neurotoxin daunorubicin. We report that activity-dependent ablation of a neuronal ensemble in the infralimbic but not the prelimbic subregion induced excessive alcohol seeking. The targeted neuronal ensemble was specific for the cue-induced response because stress-induced reinstatement was not affected in these animals. Importantly, nonselective inactivation of infralimbic neurons, using pCAG-lacZ rats, was without functional consequence on the cue-induced reinstatement task. Thus, inhibitory control over alcohol seeking is exerted by distinct functional ensembles within the infralimbic cortex rather than by a general inhibitory tone of this region on the behavioral output. This indicates a high level of functional compartmentation within the rat mPFC whereat many functional ensembles could coexist and interact within the same subregion.

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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...