Effect of morphine dependence and withdrawal on operant social interaction in male and female rats.

Opioid addiction is linked to decreased social connections. In preclinical models, non-contingent experimenter-administered morphine decreases unconditioned social interaction and place preference for social reward. We tested if these effects generalize to an operant rat model of social self-administration in which rats work volitionally for access to a peer. Based on the literature, we also tested if a kappa opioid receptor (KOR) antagonist (LY2456302) and serotonin and dopamine reuptake inhibitors (fluoxetine and GBR12909), would independently reverse the effect of morphine exposure on social self-administration. We trained rats (n = 66; 32 females) to lever-press (fixed-ratio 1 reinforcement schedule, 45min, every-other-day) for 15-s access to a peer followed by lever-pressing for food, as a control. In Experiments 1-3, we assessed self-administration during opioid dependence (~16h post-injection), and after early (2-to-6 days) and protracted (21-28 days) withdrawal with different morphine exposure regimens (0-to-80 mg/kg, s.c., twice daily; 0-to-80 mg/kg, once daily; or 0-to-40 mg/kg, every-other-day). In Experiment 4, we tested the effects of LY2456302, fluoxetine, and GBR12909 on self-administration during morphine exposure (every-other-day, 0-to-30 mg/kg). Social interaction functioned as an operant reinforcer. Both social and food self-administration were decreased during morphine exposure (dependence state) but not during early or protracted withdrawal. None of the tested compounds (LY2456302: 5, 10mg/kg, s.c.; fluoxetine: 1, 3mg/kg, i.p.; GBR12909: 3, 10mg/kg, i.p.) reversed this effect. Opioid dependence, but not withdrawal, decreased operant social interaction and food self-administration in male and female rats. This effect appears independent of KOR, serotonin, or dopamine signaling.