The need to incorporate polysubstance use in neuropsychopharmacology research: Biological lessons and new opportunities.

Critical evaluation and refinement of animal models is essential for neuroscientists to understand complex physiological and pathological processes related to psychiatric diseases. In general, preclinical studies modeling drug dependence and problematic substance use have been limited to the administration of a single substance; however, there is a growing appreciation that this approach has failed to capture the complexities of humans and has stifled translational efforts. Polysubstance use represents the overwhelmingly common patterns of alcohol and drug use in humans. For example, epidemiological studies generally determine that between 70-95 % of individuals with alcohol use disorder use tobacco daily, and upwards of 60 % of individuals who use cocaine have a comorbid alcohol use disorder. Based on this, it is imperative for preclinical researchers to consider incorporating nicotine, alcohol, and other drugs into preclinical models of drug use. Here, we discuss the complexities of polysubstance use in the real-world and in rodent models, describing core findings from recent studies that illustrate how the neurobiological mechanisms that drive polysubstance use can differ critically from monosubstance use. Despite these compelling data that justify the support for polysubstance use research, these studies face systemic challenges and barriers to funding that have throttled research in this area. We bring these challenges to light and identify new opportunities for improving the rigor and reproducibility of polysubstance use research in animal models.