Modest Long‐Term Ethanol Consumption Affects Expression of Neurotransmitter Receptor Genes in the Rat Nucleus Accumbens

Abstract

Background: Over 100 million people worldwide are affected by alcohol use disorders. These conditions usually take years to develop where an initial, voluntary consumption is gradually replaced by a compulsive intake of alcohol. The exact mechanisms behind this transition remain unknown. However, ethanol (EtOH) is known to interact with several neurotransmitters and receptors in the central nervous system, and chronic EtOH consumption causes alterations in these neurotransmitter systems, proposed to contribute to the development of dependence. This study aimed to repeat previous findings that animals after long-term voluntary EtOH consumption spontaneously increase their intake. That the initial encounter with EtOH causes an elevation of dopamine in the nucleus accumbens (nAc), inducing feelings of well-being and creating an incentive to continue the behavior, has been repeatedly reported in both animals and humans. The effects of chronic EtOH consumption on this region are not as well investigated.Methods: We examined both long-term EtOH consumption behavior and its consequences on expression of neurotransmitter-related genes in the nAc of the Wistar rat using quantitative polymerase chain reaction.Results: In general, the EtOH consumption of the animals in this study was modest with an average intake of 0.9 g/kg/d, and only 1 of the 24 rats consuming EtOH for 10 months drastically increased its intake in line with the results of Wolffgramm and Heyne (1995). Expression of the genes for dopamine receptor 2, l-opioid receptor, and somatostatin receptor 4 were down-regulated in animals after 2 and/ or 4, but not 10, months of EtOH consumption.Conclusions: Chronic consumption even of modest amounts of alcohol seems to affect regulation of expression of these genes, possibly leading to changes in neurotransmitter signaling. Studies are ongoing to investigate whether these alterations are specific for the nAc.

Mu-opioid receptor activation in the medial shell of nucleus accumbens promotes alcohol consumption, self-administration and cue-induced reinstatement

“…It is also possible that if we had assessed palatability using a taste reactivity test, rather than lickometer analysis we would have found a different result. Changes in MOR levels in the NAc due to alcohol exposure may account for the lack of altered palatability or other effects reported here: mu-opioid receptor gene expression is reported to increase after 2 and 4 months of moderate alcohol pre-exposure (similar to the levels seen here) (Jonsson et al, 2014), though decreases in MOR expression (Saland et al, 2005) or no change (Shah et al, 1997) have been reported with other sets of exposure parameters. Finally, DAMGO’s lack of effect on palatability-related measures of alcohol consumption may be related in part to the taste of alcohol functioning as a conditioned reinforcer, rather than as a primary reinforcer, or to its mixed hedonic and aversive taste qualities (Bice et al, 1992).…”

Transcriptional profiling of the rat nucleus accumbens after modest or high alcohol exposure

“…The lack of strong transcriptomic alterations in NAc is in line with other related studies in the same region [10, 24, 25], which is somewhat surprising since the NAc repeatedly is considered as one of the main regions involved in addictions, including alcoholism [26, 27]. This is indicative of region and temporal dependent molecular changes that might lead to addiction [9, 28], since numerous alterations have been found in other areas such as the prefrontal cortex and amygdala [10–12, 29]. …”

“…A total of 22 male outbred Wistar rats (Taconic, Ejby, Denmark), weighing 160-180g at the start of experiments were single housed during eight weeks, a time period previously reported to be sufficient for the detection of potential alcohol-induced alterations in gene expression [9]. Animals were housed with a regular 12h light cycle and had ad lib access to tap water and rodent chow (Lantmännen, Stockholm, Sweden).…”

“…From these studies, it seems clear that the model applied is of importance for the outcome [12–14], as the results appear to diverge between voluntary alcohol consumption and forced intake through alcohol vapour [9, 11], as well as between the rat strain used and even between animal suppliers providing a certain strain [15, 16]. Different rat strains also display different alcohol metabolism [17].…”

Dopamine and Alcohol Dependence: From Bench to Clinic

“…The dopamine deficiency hypothesis is supported by a study showing decreased dopamine receptor gene expression after several months of voluntary alcohol drinking [103]. In addition, microdialysis studies in freely moving outbred rats show a decreased dopamine output in the NAc, compared to age-matched alcohol-naïve controls, following 7 weeks [104] and 10 months [29] of voluntary alcohol consumption.…”