Inbred rat heredity and sex affect oral oxycodone self-administration and augmented intake in long sessions: correlations with anxiety and novelty-seeking

Abstract

Oxycodone abuse begins with prescription oral oxycodone, yet vulnerability factors determining abuse are largely undefined. We evaluated genetic vulnerability in a rat model of oral oxycodone self-administration (SA): increasing oxycodone concentration/session (0.025-0.1mg/ml; 1,4,16-h) followed by extinction and reinstatement. Active licks and oxycodone intake were greater in females than males during 4-h and 16-h sessions (p< 0.001). Each sex increased intake during 16-h vs 4-h sessions (p<2e-16), but a subset of strains dramatically augmented intake at 16-h (p=0.0005). Heritability (h2) of active licks/4-h at increasing oxycodone dose ranged from 0.30-0.53. Under a progressive ratio schedule, breakpoints were strain-dependent (p<2e-16). Cued reinstatement was greater in females (p<0.001). Naive rats were assessed by elevated plus maze (EPM), open field (OF) and novel object interaction (NOI). We correlated these behaviors with 28 parameters of oxycodone SA. Anxiety-defining EPM traits were most associated with SA in both sexes, whereas more OF and NOI traits were SA-associated in males. Sex and heredity are major determinants of motivation to take and seek oxycodone; intake augments dramatically during extended access in specific strains; and pleiotropic genes affect anxiety and multiple SA parameters.