Genetically selected Marchigian Sardinian alcohol-preferring (msP) rats: an animal model to study the neurobiology of alcoholism

Abstract

The present article provides an up-to-date review summarizing almost 18 years of research in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. The results of this work demonstrate that msP rats have natural preference for ethanol characterized by a spontaneous binge-type of drinking that leads to pharmacologically significant blood ethanol levels. This rat line is highly vulnerable to relapse and presentation of stimuli predictive of alcohol availability or foot-shock stress can reinstate extinguished drug-seeking up to 8 months from the last alcohol experience. The msP rat is highly sensitive to stress, shows an anxious phenotype and has depressive-like symptoms that recover following ethanol drinking. Interestingly, these animals have an up-regulated corticotrophin releasing factor (CRF) receptor 1 system. Clinical studies have shown that alcoholic patients often drink ethanol in the attempt to self-medicate from negative affective states and to search for anxiety relief. We propose that msP rats represent an animal model that largely mimics the human alcoholic population that due to poor ability to engage in stress-coping strategies drink ethanol as a tension relief strategy and for self-medication purposes.

Figure 1

Typical pattern of 10% ethanol consumption in three different msP rats. Drinking was recorded on the first day (day 1) and seventh day (day 7) of alcohol access. Measurements were carried out every hour during the dark phase of the light/dark cycle. Ethanol intake is expressed as g/kg to reduce the influence of differences in body weight

Figure 2

Alcohol-seeking behavior of msP rats induced by (a) foot-shock stress and (b) re-exposure to the alcohol (CS⁺/S⁺)- or water (CS⁻/S⁻)-paired cues. Animals were tested for reinstatement immediately after extinction (Immediate Relapse) or after 4 and 8 months. Between the different relapse the animals were kept in their home cages in the vivarium. Each test was preceded by an extinction cycle to re-establish responding consistent with the extinction criterion. Values represent the mean (± SEM) number of responses at the active lever. Difference from extinction was set at *P < 0.05 and **P < 0.01

Figure 3

Performance of msP and Wistar rats on alcohol self-administration under: (a) fixed ratio 1 schedule and (b) progressive ratio schedule. In the progressive ratio the number of responses at the lever required to obtain a single dose (0.1 ml) of 10% w/v ethanol increases progressively. (c) Behavior of msP and Wistar rats under repeated reinstatement tests. Animals were first trained to discriminate the availability of ethanol versus water in the presence of cues predictive of their availability (CS⁺/S⁺ and CS⁻/S⁻, respectively). At completion of the discrimination phase, and after an extinction period (no cues present), the CS⁺/S⁺ and/or CS⁻/S⁻ were re-presented to the animals and their behavior motivated by the stimuli predictive of ethanol (CS⁺/S⁺) versus water (CS⁺/S⁺) availability was monitored. For the reinstatement test fluids were not available. Values represent the mean (± SEM) number of responses at the active lever. Statistical difference was set at *P < 0.05 and **P < 0.01 between msP and Wistar rats, and ^#P < 0.05 and ^##P < 0.01 from extinction

Figure 4

Heatmap visualization of significant genes related to functional groups. Statistically enriched GO Ontology terms and KEGG pathways were placed against genes differentially between the two strains. Red color indicates the functional categories correlated with the genes

Figure 5

Mapk signaling pathway from KEGG. Red shaded genes are differentially expressed in Marchigian Sardinian alcohol-preferring (msP) compared with Wistars