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

Abstract

Opioid addiction is linked to decreased social connections. In preclinical models, non-contingent experimenter-administered morphine both 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 for 15-s access to a peer (fixed ratio 1 reinforcement schedule, 45 min, every other day). In Experiments 1-3, we assessed social self-administration during opioid dependence ([~]16 h 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 social self-administration during morphine exposure (every-other-day, 0-to-30 mg/kg). As in our previous studies, social interaction functioned as an operant reinforcer. Operant social interaction was decreased during morphine exposure (dependence state) but not during early or protracted withdrawal. None of the tested compounds (LY2456302: 5, 10 mg/kg, s.c.; fluoxetine: 1, 3 mg/kg, i.p.; GBR12909: 3, 10 mg/kg, i.p.) reversed this effect. Opioid dependence, but not withdrawal, decreased operant social interaction in male and female rats. This effect appears independent of KOR, serotonin, or dopamine signaling. HighlightsO_LIOpioid dependence decreased operant social interaction C_LIO_LIEarly and protracted withdrawal had no effect on operant social interaction C_LIO_LIPharmacological manipulations of Dyn, DA, and 5-HT did not restore social behavior C_LI