Sex and heredity are determinants of oral oxycodone self-administration in 36 Inbred Rat Strains: correlations with behavioral tests of anxiety and novelty-seeking

Abstract

AbstractMost individuals affected in the national epidemic of oxycodone abuse began taking oral oxycodone by prescription. We studied vulnerability to oxycodone intake in a rat model of oral drug self-administration (SA), since pharmacokinetics affect abuse potential. Females (33 inbred strains) and males (26) obtained oxycodone at increasing concentrations in operant sessions (FR5; 1-16-h) followed by extinction and reinstatement. Active spout licks were greater in females than males during 4-h and 16-h sessions (p< 0.001 for all). Across all stages of oxycodone SA, intake/session was greater in females (p<0.001). Both sexes escalated intake during 16-h extended access vs 4-h sessions (p<2e-16). Intake and active licks varied greatly by strain. The heritability (h2) of active licks/4-h at increasing oxycodone dose was larger in males (h2females: 0.30-0.39 vs. males: 0.41-0.53). Under a progressive ratio schedule, breakpoints differed by strain (p<2e-16) and by sex in some strains (p=0.018). For cue-induced reinstatement, active licks were greater in females than males (p<0.001). Behavior in naive rats was assessed using elevated plus maze (EPM), open field (OF) and novel object interaction. (NOI) tests. We correlated these behaviors with 28 parameters of oxycodone SA. EPM-defining traits were most commonly associated with SA in both sexes, whereas more OF and NOI traits were SA-associated in males. Overall, sex and heredity are major determinants of the motivation to take and seek oxycodone, which escalates during extended access. The correlation of EPM, a measure of anxiety, with multiple SA parameters indicates the influence of pleiotropic genes.