Anxiety and risk-taking behavior maps onto opioid and alcohol polysubstance consumption patterns in male and female mice.

Polysubstance use is prevalent in the population but remains understudied in preclinical models. Alcohol and opioid polysubstance use is associated with negative outcomes, worse treatment prognosis, and higher overdose risk; but underlying mechanisms are still being uncovered. Examining factors that motivate use of one substance over another in different contexts in preclinical models will better our understanding of polysubstance use and improve translational value. Here we assessed baseline anxiety-like and locomotive behavior and then measured voluntary consumption of multiple doses of alcohol and fentanyl in group housed male and female mice using our novel Socially Integrated Polysubstance (SIP) system. Fifty-six male (n=32) and female (n=24) adult mice were housed in groups of 4 for one week with continuous access to food, water, two doses of ethanol (5% and 10%) and two doses of fentanyl (5 ug/ml and 20 ug/ml). Our analyses revealed sex differences across multiple domains - female mice consumed more liquid in the dark cycle, had higher activity, a higher preference for both ethanol and fentanyl over water, and their fentanyl preference increased over the seven days. We then used machine-learning techniques to reveal underlying relationships between baseline behavioral phenotypes and subsequent polysubstance consumption patterns, where anxiety-and risk-taking-like behavioral phenotypes mapped onto discrete patterns of polysubstance use, preference, and escalation. By simulating more translationally relevant substance use and improving our understanding of the motivations for different patterns of consumption, this study contributes to the developing preclinical literature on polysubstance use with the goal of facilitating better treatment outcomes and novel therapeutic strategies.

Repetitive Blast Exposure Increases Appetitive Motivation and Behavioral Inflexibility in Male Mice.

Blast exposure (via detonation of high explosives) represents a major potential trauma source for Servicemembers and Veterans, often resulting in mild traumatic brain injury (mTBI). Executive dysfunction (e.g., alterations in memory, deficits in mental flexibility, difficulty with adaptability) is commonly reported by Veterans with a history of blast-related mTBI, leading to impaired daily functioning and decreased quality of life, but underlying mechanisms are not fully understood and have not been well studied in animal models of blast. To investigate potential underlying behavioral mechanisms contributing to deficits in executive functioning post-blast mTBI, here we examined how a history of repetitive blast exposure in male mice affects anxiety/compulsivity-like outcomes and appetitive goal-directed behavior using an established mouse model of blast mTBI. We hypothesized that repetitive blast exposure in male mice would result in anxiety/compulsivity-like outcomes and corresponding performance deficits in operant-based reward learning and behavioral flexibility paradigms. Instead, results demonstrate an increase in reward-seeking and goal-directed behavior and a congruent decrease in behavioral flexibility. We also report chronic adverse behavioral changes related to anxiety, compulsivity, and hyperarousal. In combination, these data suggest that potential deficits in executive function following blast mTBI are at least in part related to enhanced compulsivity/hyperreactivity and behavioral inflexibility and not simply due to a lack of motivation or inability to acquire task parameters, with important implications for subsequent diagnosis and treatment management.