Following exposure to traumatic events, only a small proportion of individuals (susceptible individuals) develops post-traumatic stress disorder (PTSD), while the others remain weakly affected (resilient individuals). In susceptible individuals, there is a high rate of co-morbidity with substance use disorder (SUD), especially with alcohol and cocaine use. Knowing that current treatments to reduce PTSD symptoms in co-morbid conditions show little efficacy, understanding the mechanisms underlying the individual differences and interactions between PTSD and SUD is needed to develop effective treatments. Thus, our work, carried out with rodent models aimed initially to elucidate the behavioral and neurobiological differences between the susceptible and the resilient phenotypes and to explore the consequences of exposure to alcohol on PTSD symptoms. Second, we studied the effects of chronic alcohol or cocaine use on PTSD. Finally, we tested the effectiveness of topiramate in co-morbid conditions. Our results show that the susceptible and resilient phenotypes are distinguished by opposite dendritic changes in the prelimibic (PrL) and infralimbic (IL) regions of the median prefrontal cortex (mPFC). These changes are associated with high levels of ACTH and corticosterone and low levels of BDNF. The consequences of comorbidity are the persistence of symptoms, the exacerbation of dendritic changes in the PrL region and the resistant to treatment with topiramate. We therefore suggest to provide more efforts to develop means of intervention to promote resilience.