For ethical and technical reasons, research in humans has some limitations and requires the support of animal models. Numerous animal models have been developed over the years to study alcohol consumption and model alcohol-related behaviors in several species, including non-human primates, rodents and more recently zebrafish, fruit flies and C. elegans. In this chapter, we provide an overview of the most commonly used animal models of alcohol use disorder (AUD) and discuss their pros and cons. We classify animal models of AUD into two main categories, operant and non-operant paradigms, which covers behavioral procedures developed to model several aspects of human addiction, including primary alcohol reinforcement, physical dependence, loss of control over alcohol intake, progressive choice of alcohol over healthy rewards and relapse. Finally, we will conclude and discuss about other important aspects of human addiction, including interindividual differences, sex differences and social factors, that need to be incorporated into preclinical models of AUD to improve their translational value.

Animal models of substance use disorders have been criticized for their limited translation. One important factor behind seeking and taking that has so far been largely overlooked is the availability of alternative non-drug rewards. We recently reported that only about 15% of outbred Wistar rats will choose alcohol over a sweet solution of saccharin. It was also shown using a novel operant model of choice of drugs over social rewards that social interaction consistently attenuates self-administration and incubation of craving for stimulants and opioids. Whether this is also true for alcohol and choice of alcohol over a sweet reward translates to social rewards is currently unknown. We therefore evaluated choice between alcohol and a social reward in different experimental settings in both male and female Wistar rats. We found, in contrast to prior work that employed discrete choice of drugs vs. social reward, that rats almost exclusively prefer alcohol over social interaction, irrespective of the nature of the social partner (cagemate vs. novel rat), the length of interaction, housing conditions and sex. Alcohol choice was reduced when the response requirement for alcohol was increased. However, rats persisted in choosing alcohol, even when the effort required to obtain it was 10-16 times higher (for females and males respectively) than the one for the social reward. Altogether, these results indicate that the social choice model may not generalize to alcohol, pointing to the possibility that specific interactions between alcohol and social reward, not seen when a sweet solution is used as an alternative to the drug, may play a crucial role in alcohol vs. social choice experiments.

Pre- and post-trauma drug use can interfere with recovery from post-traumatic stress disorder (PTSD). However, the biological underpinnings of this interference are poorly understood. Here we examined the effect of pre-fear conditioning cocaine self-administration on PTSD-like symptoms in male rats, and defined impairment of fear extinction as difficulty to recover from PTSD. We also examined cell density changes in brain regions suspected of being involved in resistance to PTSD recovery. Before footshock stress testing, rats were trained to self-administer cocaine during 20 consecutive days, after which they were exposed to footshocks, while other rats continued to self-administer cocaine until the end of the experiment. Upon assessment of three PTSD-like symptoms (fear during situational reminders, anxiety-like behavior, and impairment of recognition memory) and fear extinction learning and memory, changes in cell density were measured in the medial prefrontal cortex, hippocampus, and amygdala. Results show that pre-footshock cocaine exposure did not affect fear during situational reminders. Fear conditioning did not lead to an increase in cocaine consumption. However, in footshock stressed rats, cocaine induced a reduction of anxiety-like behavior, an aggravation of recognition memory decline, and an impairment of extinction memory. These behavioral alterations were associated with increased cell density in the hippocampal CA1, CA2, and CA3 regions and basolateral amygdala, but not in the medial prefrontal cortex. Our findings suggest that enhancement of cell density in the hippocampus and amygdala may be changes associated with drug use, interfering with PTSD recovery.

Treatment of post-traumatic stress disorder is complicated by the presence of alcohol use disorder comorbidity. Little is known about the underlying brain mechanisms. We have recently shown, in mice, that the post-traumatic stress disorder-like phenotype is characterised by the increase and decrease in total dendritic number and length in the prelimbic and infralimbic areas of the medial prefrontal cortex, respectively. Here, we examined whether repeated ethanol exposure would exacerbate these changes and whether this would be associated with difficulty to extinguish passive avoidance behaviour, as an indicator of treatment resistance. We also analysed whether other known trauma-associated changes, like increased or decreased corticosterone and decreased brain-derived neurotrophic factor levels, would also be exacerbated. Male mice underwent trauma exposure (1.5-mA footshock), followed, 8 days later, by a conditioned place preference training with ethanol. Tests for fear sensitization, passive avoidance, anxiety-like behaviour, extinction acquisition and relapse susceptibility were used to assess behaviour changes. Plasma corticosterone and brain-derived neurotrophic factor levels and prefrontal dendritic changes were subsequently measured. Trauma-susceptible mice exposed to ethanol acquired a strong place preference and behaved differently from those not exposed to ethanol, with delayed avoidance extinction and higher avoidance relapse vulnerability. Ethanol potentiated trauma-associated dendritic changes in the prelimbic area and suppressed trauma-associated dendritic changes in the infralimbic area. However, ethanol had no effect on trauma-induced increased corticosterone and decreased brain-derived neurotrophic factor levels. These data suggest that the modification of prefrontal trauma-related changes, due to alcohol use, can characterise, and probably support, treatment-resistant post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is triggered by exposure to traumatic events, but not everyone who experiences trauma develops this disorder. Like humans, PTSD-like symptoms develop in some laboratory rodents (susceptible individuals), while others express less or no symptoms (resilient individuals). Here, considering (i) the putative causal role of fear conditioning in PTSD development and (ii) the involvement of the medial prefrontal cortex (mPFC) in the regulation of conditioned fear response, we tested whether trauma-associated changes in the mPFC may discriminate stress-resilient from stress-susceptible mice. From data on avoidance behavior (as a major symptom), we found that trauma-exposed mice displayed a bimodal distribution in their step-through latency, with low avoider (stress-resilient) individuals and high avoider (stress-susceptible) individuals. Dendrites of Golgi–Cox-stained neurons were analyzed in two parts of the mPFC: the prelimbic (PrL) and infralimbic (IL) areas. In the resilient phenotype, the total number of dendrites decreased in the PrL and increased in the IL; however, it decreased only in the IL in the susceptible phenotype compared to controls. These findings demonstrate that the type of post-trauma morphological changes in the mPFC is associated with susceptibility or resilience to trauma-related symptoms.