Heavy alcohol drinking results in pathological alterations in the brain. An important issue is what neurotrasmitter systems are affected, and whether the produced neurotransmitter changes underlie development of alcohol dependence along with psychological and cognitive disturbances associated with alcoholism. Molecular dysregulations in the endogenous opioid, glutamate and GABAergic systems may play a role in the development of alcohol dependence and associated cognitive impairment (Koob et al., 2013). Animal models of alcohol dependence, tolerance and toxicity do not reflect all complexity of this disorder (McBride et al., 1998). Therefore in this study we aimed to assess whether these neurotransmitter systems undergo adaptive changes associated with alcoholism in the human brain. The aim was addressed by analysis of postmortem brain specimens. In the opioid system, strong and significant differences were observed in expression of the prodynorphin gene, which gives rise to precursor of opioid peptides dynorphins, but not other opioid genes. Prodynorphin expression was upregulated and dynorphins were elevated in the prefrontal cortex (PFC) and hippocampus in alcoholics. Expression of ionotropic glutamate receptors (iGlu) subunits was found to be altered in the brain of human alcoholics. Alcoholism was associated with increased expression of 10 iGlu subunits in hippocampus (HP-DG), and reduced mRNA level of 5 iGlu subunits in central amygdala (CeA) and 1 subunit mRNA in orbital frontal cortex (OFC). None of analyzed iGlu mRNAs was altered in the PFC. Furthermore, we demonstrated that alcohol consumption alters expression of several subunits of GABAa receptor and that these changes are brain region specific. mRNA levels of five GABAA receptor subunits were increased in the HP-DG, while of two and one other subunits decreased in OFC and CeA, respectively. mRNA level of 16 GABAA receptor subunits was not altered in the PFC. In conclusion, the alterations in transcription of genes of the opioid, glutamate and GABA systems identified in brain regions involved in neurocognitive control of addictive behavior may represent molecular adaptations developed after many years of alcohol consumption and withdrawal. Alternatively, these findings may reflect inherited molecular differences between controls and alcoholics. In both cases, these changes may underlie transition to alcoholism contributing to craving and compulsive alcohol seeking behavior. Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response were investigated. Genetic marker was identified, this is the minor GRIN2B rs2058878 A allele, which is associated with longer abstinence during the first 3 months of acamprosate treatment. This is an important step toward the development of personalized treatment recommendations for patients with alcohol use disorders, as genetic markers may be used for selection of patients who have the highest probability of responding to acamprosate. Key words: PDYN, OPRK1, GRIN2B, iGlu и GABA receptors, alcoholism.
