Modeling escalation of drug intake to identify molecular targets for treating substance use disorders: A slippery slope upward

Among the various checklist items used to diagnose substance use disorders (SUDs), the most recent version of the Diagnostic and Statistical Manual (DSM-5) begins with three items that imply a loss of control characterized by taking increasingly larger amounts of the drug and for longer periods. This process, often called “escalation”, has been modeled in laboratory animals with the goal of identifying the mechanisms associated with SUDs. The current review first summarizes the different interpretations used to explain escalation of drug intake. Next, we examine the various ways that escalation of intake has been defined in clinical populations and how preclinical models have captured this phenomenon in the laboratory. Next, we critically discuss the key issues relevant to statistical modeling of escalation of drug intake in both humans and non-human animals, with the goal of quantifying individual differences in escalation behavior that may be useful for identifying a SUD “phenotype”. Although both preclinical and clinical data rarely consider individual differences in escalation as a discrete factor, we also summarize findings indicating that common models of escalated drug intake are associated with specific genetic and cellular changes. Building on this framework of investigation is intended to offer insights in understanding the trajectory of SUDs, thus uncovering novel avenues for prevention and treatment.