REVIEW: The alcohol‐preferring AA and alcohol‐avoiding ANA rats: neurobiology of the regulation of alcohol drinking

Abstract

The AA (alko, alcohol) and ANA (alko, non-alcohol) rat lines were among the earliest rodent lines produced by bidirectional selection for ethanol preference. The purpose of this review is to highlight the strategies for understanding the neurobiological factors underlying differential alcohol-drinking behavior in these lines. Most early work evaluated functioning of the major neurotransmitter systems implicated in drug reward in the lines. No consistent line differences were found in the dopaminergic system either under baseline conditions or after ethanol challenges. However, increased opioidergic tone in the ventral striatum and a deficiency in endocannabinoid signaling in the prefrontal cortex of AA rats may comprise mechanisms leading to increased ethanol consumption. Because complex behaviors, such as ethanol drinking, are not likely to be controlled by single factors, system-oriented molecular-profiling strategies have been used recently. Microarray based expression analysis of AA and ANA brains and novel data-mining strategies provide a system biological view that allows us to formulate a hypothesis on the mechanism underlying selection for ethanol preference. Two main factors appear active in the selection: a recruitment of signal transduction networks, including mitogen-activated protein kinases and calcium pathways and involving transcription factors such as Creb, Myc and Max, to mediate ethanol reinforcement and plasticity. The second factor acts on the mitochondrion and most likely provides metabolic flexibility for alternative substrate utilization in the presence of low amounts of ethanol.

Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders

“…The regional specificity is interesting and in line with the microarray studies in high-preferring rats [18,19]. Inhibition of AngII production by 5 mg/kg spirapril, an ACE inhibitor that efficiently crosses the blood brain barrier and that according to experiments in Agt knockout mice reduces ethanol consumption via central Ang II action [16], was more potent in reducing ethanol intake in postdependent rats compared to controls [28].…”

“…Recent studies in animals with genetic modification in various components of the RAS demonstrate that Ang II via AT 1 action is a positive modulator of spontaneous ethanol consumption in rodents [15,16]. Furthermore, increased expression of Agt was found in microarray studies of brains from different rodent lines selectively bred for high ethanol preference (HAP mice, P and AA rats) compared to their respective controls [17][18][19]. Bioinformatic analysis of known genegene interactions among differential expressed genes in these animals identified Agt as a key node in the interaction network.…”

The effect of alcohol and nicotine abuse on gene expression in the brain

“…The down-regulation of mitochondrial genes including those associated with electron transport or energy production was revealed in two studies (64,67) . Mitochondrial function was again implicated in the animal model of alcohol preference (36) . These changes indicate that disruption of mitochondrial function may be a possible source of oxidative stress.…”

“…A promoter analysis of genes differentially expressed in the cerebellum in these strains identified cAMP response element binding (CREB) signalling to be a common feature of many of these genes (35) . In a study comparing gene expression levels in the PFC of alcohol-preferring and non-preferring rats, MAPK and CREB signalling was again associated with alcoholrelated behaviour (36) . Additionally genes concerned with mitochondrial function were differentially expressed between the rat strains (36) .…”

“…In a study comparing gene expression levels in the PFC of alcohol-preferring and non-preferring rats, MAPK and CREB signalling was again associated with alcoholrelated behaviour (36) . Additionally genes concerned with mitochondrial function were differentially expressed between the rat strains (36) . NFkB, Jun and CREB signalling as well as mitochondrial function are involved with cell survival and apoptotic events.…”