Abstract
Recent animal models of alcohol use disorder (AUD) are centered in capturing individual vulnerability differences in disease progression. Here, we used genetically selected Marchigian Sardinian alcohol-preferring (msP) and Wistars rats to apply a multidimensional model of AUD adapted from a previously described DSM-IV/DSM-5 multisymptomatic cocaine addiction model. As proof of concept, we hypothesized that msP rats, genetically selected for excessive drinking, would be more prone to develop dependence-like behavior compared to Wistars. Before exposure of animals to alcohol, we monitored basal anxiety in the elevated plus maze (EPM). Animals were then trained in prolonged operant alcohol self-administration, consisting of 30-min daily sessions for 60 days in total. Each session consisted of two 10-min periods of alcohol reinforcement separated by 10-min interval of non-reinforcement. Following training, we applied three criteria of individual vulnerability for AUD: (1) persistence of lever pressing for alcohol when it was not available; (2) motivation for alcohol in a progressive ratio (PR) schedule of reinforcement; and (3) resistance to punishment when alcohol delivery was anticipated by a foot-shock (0.3 mA). We obtained four groups corresponding to the number of criteria met (0–3 crit). Rats in the 0crit and 1crit groups were characterized as resilient, whereas rats in the 2crit and 3crit groups were characterized as prone to develop a dependent-like phenotype. As predicted, the 2–3crit groups were enriched with msP rats while the 0–1crit groups were enriched in Wistar rats. In further analysis, we calculated the global addiction score (GAS) per subject by the sum of the normalized score (z-score) of each criterion. Results showed GAS was highly correlated with animal distribution within the 3 criteria. Specifically, GAS was negative in the 0–1crit groups, and positive in the 2–3crit groups. A positive correlation between basal anxiety and quantity of alcohol intake was detected in msP rats but not Wistars. In conclusion, we demonstrated that the 0/3criteria model is a suitable approach to study individual differences in AUD and that msP rats, selected for excessive-alcohol drinking, show a higher propensity to develop AUD compared to non-preferring Wistars.
Highlights
Alcohol Use Disorder (AUD) is associated with increased health risks and social harm with dramatic impact to the global disease burden (Rehm, 2011)
ANOVA of number of rewards earned revealed a significant effect of line (F(1,61) = 83.3; p < 0.001), significant effect of session (F(59,3599) = 100.31; p < 0.001) and a significant line × session interaction (F(53,3599) = 5.71; p < 0.001). Marchigian Sardinian alcohol-preferring (msP) rats self-administered significantly more ethanol compared to Wistars
A valid animal model that attempts to reflect the human condition in addiction should capture multiple aspects that characterize substance use disorders (SUDs) such as compulsive drug seeking and taking, increased motivation for the drug, and continued intake despite negative consequences (Hopf and Lesscher, 2014)
Summary
Alcohol Use Disorder (AUD) is associated with increased health risks and social harm with dramatic impact to the global disease burden (Rehm, 2011). In order to identify the interindividual differences in vulnerability to shift from controlled to compulsive drug intake that define this subpopulation, DerocheGamonet et al (2004) developed a multidimensional animal model of drug addiction (Belin-Rauscent et al, 2016; DerocheGamonet et al, 2004; Belin et al, 2008, 2009, 2011) This model characterized a cocaine addiction-prone phenotype in rats, based on the DSM-IV diagnostic criteria of addiction (American Psychiatric Association, 2000), by measuring three traits: (1) inability to refrain from drug seeking; (2) high motivation for the drug; and (3) maintenance of drug use despite negative consequences (Deroche-Gamonet et al, 2004; Kasanetz et al, 2010; Belin et al, 2011). Based on these conceptualizations we predicted that msP rats, genetically selected for excessive drinking, would be more prone to develop dependence-like behavior compared to Wistars
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