Aged mice exhibit more rapid acquisition of remifentanil self-administration and an up-shifted dose-response curve

Abstract

<b>Abstract ID 21544</b> <b>Poster Board 65</b> Opioid use disorder is a chronic, relapsing condition characterized by cycles of voluntary abstinence, the appearance of withdrawal symptoms, and subsequent reinstatement of intake. Current medical approaches are not sufficient to help abstinent addicts that wish to prevent entering their next cycle of use. Although opioid use disorder is more common in the young, aged individuals are more likely to experience chronic pain, predisposing them to increased risk of becoming addicted to prescription or illicit painkillers. However, drug self-administration studies in rodents have historically only used young animals, and to our knowledge no study has explored intravenous opioid self-administration in an aged rodent model. Here we trained young (3-4 month) and old (20-24 month) C57Bl/6N mice to operantly respond for intravenous infusions of the fast-acting opioid remifentanil (3 or 10 μg/kg/infusion during training). Nearly all mice acquired self-administration at both doses, however acquisition was significantly more rapid in old mice at the 3 μg/kg/infusions dose (<i>P</i> = 0.015). We then put mice through a multi-day dose-response curve in 3-hr FR3 sessions (1-100 μg/kg/infusion, 2-3 days per dose). Old mice exhibited significantly up-shifted responding and intake compared to young mice (<i>P</i> = 0.0008). Finally, mice were given a single 3-hr session where correct responses elicited light and sound cues previously associated with remifentanil after either 1 or 30 days of forced abstinence, but no drug infusion occurred. Both young and old mice showed significantly more responding for cues at 30 days versus 1 day of abstinence (<i>P</i> = 0.018) with no main effect of age. No sex differences were apparent in any measure. This is the first demonstration of incubation of remifentanil craving in any rodent model of self-administration and indicates increased drug seeking following forced abstinence. The up-shifted dose-response relationship is consistent with differences in hedonic setpoint and could indicate a general phenotype of drug abuse vulnerability in the aged population. Further work will be needed to test the applicability to other opioids and other classes of abused drug. Funded by NIH R21 AG072811 and VA Merit Review Award I01 BX005396.